{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:49:33Z","timestamp":1787028573202,"version":"build-2736575974"},"reference-count":199,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T00:00:00Z","timestamp":1760313600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"crossref","award":["RS-2021-NR060117"],"award-info":[{"award-number":["RS-2021-NR060117"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"crossref","award":["2021R1A6A1A03038996"],"award-info":[{"award-number":["2021R1A6A1A03038996"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Frontotemporal dementia (FTD) is the second most common early-onset dementia after Alzheimer\u2019s disease, characterized by progressive neurodegeneration primarily in the frontal and temporal lobes. Granulin (GRN) gene for encoding the progranulin (PGRN) protein was a key genetic contributor to FTD. PGRN was a multifunctional protein involved in lysosomal function, neuroinflammation, and neuronal survival. This review discusses the contributions of GRN haploinsufficiency to FTD pathogenesis with an emphasis on genetic mutations, downstream cellular consequences, relevant animal and cellular models, and emerging therapeutic strategies. Loss-of-function mutations in GRN were responsible up to ~50% reduction in PGRN levels, resulting in lysosomal dysfunction, TDP-43 aggregation, impaired microglial homeostasis, and enhanced neuroinflammation. Multiple in vitro and in vivo models recapitulated these pathological features. Novel therapeutic approaches, such as AAV-mediated gene therapy, stop codon readthrough compounds, SORT1 inhibitors, and antisense oligonucleotides, were investigated to restore PGRN levels and to mitigate disease progressions. However, challenges included the oncogenic risks of overexpression and the limited translational success in clinical trials to date. Targeting GRN haploinsufficiency became a promising avenue for FTD therapy. Improved models and refined delivery systems would be essential to develop safe and effective treatments. Future work should also focus on biomarker-guided interventions in presymptomatic mutation carriers.<\/jats:p>","DOI":"10.3390\/ijms26209960","type":"journal-article","created":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T16:13:03Z","timestamp":1760717583000},"page":"9960","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Targeting Granulin Haploinsufficiency in Frontotemporal Dementia: From Genetic Mechanisms to Therapeutics"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0487-8668","authenticated-orcid":false,"given":"Eva","family":"Bagyinszky","sequence":"first","affiliation":[{"name":"Graduate School of Environment Department of Industrial and Environmental Engineering, Gachon University, Seongnam 13120, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8123-6183","authenticated-orcid":false,"given":"Seong Soo A.","family":"An","sequence":"additional","affiliation":[{"name":"Department of Bionano Technology, Gachon Medical Research Institute, Gachon University, Seongnam 13120, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1016\/S1474-4422(14)70065-1","article-title":"Frontotemporal dementia and its subtypes: A genome-wide association study","volume":"13","author":"Ferrari","year":"2014","journal-title":"Lancet Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3048","DOI":"10.1093\/brain\/awae067","article-title":"Atrophy network mapping of clinical subtypes and main symptoms in frontotemporal dementia","volume":"147","author":"Chu","year":"2024","journal-title":"Brain"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1212\/CON.0000000000000300","article-title":"Frontotemporal Dementias","volume":"22","author":"Finger","year":"2016","journal-title":"Contin. Lifelong Learn. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1136\/jnnp.57.4.416","article-title":"Clinical and neuropathological criteria for frontotemporal dementia. The Lund and Manchester Groups","volume":"57","author":"Englund","year":"1994","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Abramzon, Y.A., Fratta, P., Traynor, B.J., and Chia, R. (2020). The Overlapping Genetics of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Front. Neurosci., 14.","DOI":"10.3389\/fnins.2020.00042"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"49","DOI":"10.3233\/JAD-121969","article-title":"Overlap between frontotemporal dementia and Alzheimer\u2019s disease: Cerebrospinal fluid pattern and neuroimaging study","volume":"36","author":"Padovani","year":"2013","journal-title":"J. Alzheimers Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2075","DOI":"10.1007\/s00415-019-09363-4","article-title":"An update on genetic frontotemporal dementia","volume":"266","author":"Greaves","year":"2019","journal-title":"J. Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"23","DOI":"10.3233\/JAD-2012-120946","article-title":"GRN Variant rs5848 Reduces Plasma and Brain Levels of Granulin in Alzheimer\u2019s Disease Patients","volume":"33","author":"Viswanathan","year":"2012","journal-title":"J. Alzheimers Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1007\/s11910-012-0268-5","article-title":"Recent advances in the genetics of the ALS-FTLD complex","volume":"12","author":"Morris","year":"2012","journal-title":"Curr. Neurol. Neurosci. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Karamysheva, Z.N., Tikhonova, E.B., and Karamyshev, A.L. (2019). Granulin in Frontotemporal Lobar Degeneration: Molecular Mechanisms of the Disease. Front. Neurosci., 13.","DOI":"10.3389\/fnins.2019.00395"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1110\/ps.073295308","article-title":"Structure dissection of human progranulin identifies well-folded granulin\/epithelin modules with unique functional activities","volume":"17","author":"Tolkatchev","year":"2008","journal-title":"Protein Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2247","DOI":"10.1073\/pnas.1609243114","article-title":"Atomic structure of granulin determined from native nanocrystalline granulovirus using an X-ray free-electron laser","volume":"114","author":"Gati","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1038\/nrn.2017.36","article-title":"Progranulin, lysosomal regulation and neurodegenerative disease","volume":"18","author":"Kao","year":"2017","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Zhou, X., Paushter, D.H., Feng, T., Sun, L., Reinheckel, T., and Hu, F. (2017). Lysosomal processing of progranulin. Mol. Neurodegener., 12.","DOI":"10.1186\/s13024-017-0205-9"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Mohan, S., Sampognaro, P.J., Argouarch, A.R., Maynard, J.C., Welch, M., Patwardhan, A., Courtney, E.C., Zhang, J., Mason, A., and Li, K.H. (2021). Processing of progranulin into granulins involves multiple lysosomal proteases and is affected in frontotemporal lobar degeneration. Mol. Neurodegener., 16.","DOI":"10.1186\/s13024-021-00472-1"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Du, H., Zhou, X., Feng, T., and Hu, F. (2022). Regulation of lysosomal trafficking of progranulin by sortilin and prosaposin. Brain Commun., 4.","DOI":"10.1093\/braincomms\/fcab310"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Zheng, Y., Brady, O.A., Meng, P.S., Mao, Y., and Hu, F. (2011). C-terminus of progranulin interacts with the beta-propeller region of sortilin to regulate progranulin trafficking. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0021023"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1016\/j.molmed.2017.08.004","article-title":"Modifiers of GRN-Associated Frontotemporal Lobar Degeneration","volume":"23","author":"Wauters","year":"2017","journal-title":"Trends Mol. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2339","DOI":"10.1002\/ijc.22559","article-title":"Prosurvival function of the granulin-epithelin precursor is important in tumor progression and chemoresponse","volume":"120","author":"Pizarro","year":"2007","journal-title":"Int. J. Cancer"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Arechavaleta-Velasco, F., Perez-Juarez, C.E., Gerton, G.L., and Diaz-Cueto, L. (2017). Progranulin and its biological effects in cancer. Med. Oncol., 34.","DOI":"10.1007\/s12032-017-1054-7"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1073\/pnas.89.5.1715","article-title":"Isolation and sequence of the granulin precursor cDNA from human bone marrow reveals tandem cysteine-rich granulin domains","volume":"89","author":"Bhandari","year":"1992","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Horinokita, I., Hayashi, H., Oteki, R., Mizumura, R., Yamaguchi, T., Usui, A., Yuan, B., and Takagi, N. (2019). Involvement of Progranulin and Granulin Expression in Inflammatory Responses after Cerebral Ischemia. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20205210"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1212\/WNL.0000000000004840","article-title":"Progranulin: Functions and neurologic correlations","volume":"90","author":"Townley","year":"2018","journal-title":"Neurology"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Du, H., Wong, M.Y., Zhang, T., Santos, M.N., Hsu, C., Zhang, J., Yu, H., Luo, W., and Hu, F. (2021). A multifaceted role of progranulin in regulating amyloid-beta dynamics and responses. Life Sci. Alliance, 4.","DOI":"10.1101\/2021.04.12.439509"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"632","DOI":"10.2174\/157015911798376361","article-title":"Recent insights into the involvement of progranulin in frontotemporal dementia","volume":"9","author":"Sun","year":"2011","journal-title":"Curr. Neuropharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1002\/humu.20651","article-title":"Progranulin locus deletion in frontotemporal dementia","volume":"29","author":"Gijselinck","year":"2008","journal-title":"Hum. Mutat."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1093\/jnen\/nlx085","article-title":"Disease and Region Specificity of Granulin Immunopositivities in Alzheimer Disease and Frontotemporal Lobar Degeneration","volume":"76","author":"Mao","year":"2017","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Ryan, C.L., Baranowski, D.C., Chitramuthu, B.P., Malik, S., Li, Z., Cao, M., Minotti, S., Durham, H.D., Kay, D.G., and Shaw, C.A. (2009). Progranulin is expressed within motor neurons and promotes neuronal cell survival. BMC Neurosci., 10.","DOI":"10.1186\/1471-2202-10-130"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Ahmed, Z., Mackenzie, I.R., Hutton, M.L., and Dickson, D.W. (2007). Progranulin in frontotemporal lobar degeneration and neuroinflammation. J. Neuroinflamm., 4.","DOI":"10.1186\/1742-2094-4-7"},{"key":"ref_30","first-page":"969","article-title":"Progranulin regulates lysosomal function and biogenesis through acidification of lysosomes","volume":"26","author":"Tanaka","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1002\/bies.200900086","article-title":"The granulin gene family: From cancer to dementia","volume":"31","author":"Bateman","year":"2009","journal-title":"BioEssays"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1002\/humu.20785","article-title":"Granulin mutations associated with frontotemporal lobar degeneration and related disorders: An update","volume":"29","author":"Gijselinck","year":"2008","journal-title":"Hum. Mutat."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1007\/s00401-009-0576-2","article-title":"Brain progranulin expression in GRN-associated frontotemporal lobar degeneration","volume":"119","author":"Xiao","year":"2010","journal-title":"Acta Neuropathol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Hashimoto, K., Jahan, N., Miller, Z.A., and Huang, E.J. (2022). Neuroimmune dysfunction in frontotemporal dementia: Insights from progranulin and C9orf72 deficiency. Curr. Opin. Neurobiol., 76.","DOI":"10.1016\/j.conb.2022.102599"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"159","DOI":"10.3233\/JAD-180599","article-title":"Peripheral GRN mRNA and Serum Progranulin Levels as a Potential Indicator for Both the Presence of Splice Site Mutations and Individuals at Risk for Frontotemporal Dementia","volume":"67","author":"Guven","year":"2019","journal-title":"J. Alzheimers Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.neurobiolaging.2023.06.009","article-title":"Rare exonic variant affects GRN splicing and contributes to frontotemporal lobar degeneration","volume":"130","author":"Wauters","year":"2023","journal-title":"Neurobiol. Aging."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1001\/archneur.64.10.1436","article-title":"Alzheimer and Parkinson diagnoses in progranulin null mutation carriers in an extended founder family","volume":"64","author":"Brouwers","year":"2007","journal-title":"Arch. Neurol."},{"key":"ref_38","first-page":"57","article-title":"A variant in GRN of Spanish origin presenting with heterogeneous phenotypes","volume":"40","author":"Pitiot","year":"2022","journal-title":"Neurologia"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1001\/archneurol.2009.328","article-title":"The spectrum of mutations in progranulin: A collaborative study screening 545 cases of neurodegeneration","volume":"67","author":"Yu","year":"2010","journal-title":"Arch. Neurol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Almeida, M.R., T\u00e1buas-Pereira, M., Baldeiras, I., Lima, M., Dur\u00e3es, J., Massano, J., Pinto, M., Cruto, C., and Santana, I. (2023). Characterization of Progranulin Gene Mutations in Portuguese Patients with Frontotemporal Dementia. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25010511"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1093\/brain\/awn012","article-title":"Phenotype variability in progranulin mutation carriers: A clinical, neuropsychological, imaging and genetic study","volume":"131","author":"Camuzat","year":"2008","journal-title":"Brain"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"25879","DOI":"10.1074\/jbc.M114.560128","article-title":"Progranulin transcripts with short and long 5\u2032 untranslated regions (UTRs) are differentially expressed via posttranscriptional and translational repression","volume":"289","author":"Capell","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e9","DOI":"10.1016\/j.neurobiolaging.2019.06.002","article-title":"The missense p.Trp7Arg mutation in GRN gene leads to progranulin haploinsufficiency","volume":"85","author":"Saracino","year":"2020","journal-title":"Neurobiol. Aging"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2844","DOI":"10.1016\/j.celrep.2018.05.003","article-title":"Pathogenic Signal Sequence Mutations in Progranulin Disrupt SRP Interactions Required for mRNA Stability","volume":"23","author":"Pinarbasi","year":"2018","journal-title":"Cell Rep."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.jns.2010.10.009","article-title":"rs5848 polymorphism and serum progranulin level","volume":"300","author":"Hsiung","year":"2011","journal-title":"J. Neurol. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1111\/j.1471-4159.2007.04968.x","article-title":"Progranulin: Normal function and role in neurodegeneration","volume":"104","author":"Eriksen","year":"2008","journal-title":"J. Neurochem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1080\/13554794.2018.1506039","article-title":"Pathological correlates of white matter hyperintensities in a case of progranulin mutation associated frontotemporal dementia","volume":"24","author":"Woollacott","year":"2018","journal-title":"Neurocase"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"485","DOI":"10.2174\/156720506779025251","article-title":"Progranulin mutations in ubiquitin-positive frontotemporal dementia linked to chromosome 17q21","volume":"3","author":"Cruts","year":"2006","journal-title":"Curr. Alzheimer Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1206","DOI":"10.1016\/j.neurobiolaging.2013.10.097","article-title":"Understanding phenotype variability in frontotemporal lobar degeneration due to granulin mutation","volume":"35","author":"Bonvicini","year":"2014","journal-title":"Neurobiol. Aging"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.neurobiolaging.2018.03.007","article-title":"Clinical variability and onset age modifiers in an extended Belgian GRN founder family","volume":"67","author":"Wauters","year":"2018","journal-title":"Neurobiol. Aging"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1016\/S1474-4422(07)70221-1","article-title":"Phenotypic variability associated with progranulin haploinsufficiency in patients with the common 1477C-->T (Arg493X) mutation: An international initiative","volume":"6","author":"Rademakers","year":"2007","journal-title":"Lancet Neurol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"939","DOI":"10.3233\/JAD-140717","article-title":"A mutation in the 5\u2032-UTR of GRN gene associated with frontotemporal lobar degeneration: Phenotypic variability and possible pathogenetic mechanisms","volume":"42","author":"Puoti","year":"2014","journal-title":"J. Alzheimers Dis."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s13195-017-0334-y","article-title":"Extended FTLD pedigree segregating a Belgian GRN-null mutation: Neuropathological heterogeneity in one family","volume":"10","author":"Sieben","year":"2018","journal-title":"Alzheimers Res. Ther."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1038\/nature05017","article-title":"Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21","volume":"442","author":"Cruts","year":"2006","journal-title":"Nature"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"717","DOI":"10.3233\/JAD-160185","article-title":"Non Fluent Variant of Primary Progressive Aphasia Due to theel GRN g.9543delA(IVS3-2delA) Mutation","volume":"54","author":"Cioffi","year":"2016","journal-title":"J. Alzheimers Dis."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1002\/humu.20681","article-title":"Molecular characterization of novel progranulin (GRN) mutations in frontotemporal dementia","volume":"29","author":"Mukherjee","year":"2008","journal-title":"Hum. Mutat."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"583","DOI":"10.3233\/JAD-2011-110332","article-title":"Variability of the clinical phenotype in an Italian family with dementia associated with an intronic deletion in the GRN gene","volume":"26","author":"Marcon","year":"2011","journal-title":"J. Alzheimers Dis."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"e9","DOI":"10.1016\/j.neurobiolaging.2019.11.008","article-title":"One novel GRN null mutation, two different aphasia phenotypes","volume":"87","author":"Coppola","year":"2020","journal-title":"Neurobiol. Aging"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"3115","DOI":"10.1093\/brain\/awl276","article-title":"Novel splicing mutation in the progranulin gene causing familial corticobasal syndrome","volume":"129","author":"Masellis","year":"2006","journal-title":"Brain"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1212\/WNL.0b013e3181bd82a7","article-title":"\u201cFrontotemporoparietal\u201d dementia: Clinical phenotype associated with the c.709-1G>A PGRN mutation","volume":"73","author":"Moreno","year":"2009","journal-title":"Neurology"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"e7","DOI":"10.1016\/j.neurobiolaging.2010.11.020","article-title":"Alteration in cell cycle-related proteins in lymphoblasts from carriers of the c.709-1G>A PGRN mutation associated with FTLD-TDP dementia","volume":"33","author":"Alquezar","year":"2012","journal-title":"Neurobiol. Aging"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"475","DOI":"10.3233\/JAD-151170","article-title":"Ael Splice-Acceptor Site Mutation in GRN (c.709-2 A>T) Causes Frontotemporal Dementia Spectrum in a Large Family from Southern Italy","volume":"53","author":"Sassi","year":"2016","journal-title":"J. Alzheimers Dis."},{"key":"ref_63","first-page":"e9","article-title":"Functional characterization of a novel progranulin mutation in a patient with progressive nonfluent aphasia","volume":"72","author":"Sitek","year":"2018","journal-title":"Neurobiol. Aging"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"341","DOI":"10.3233\/JAD-200151","article-title":"Clinical and Molecular Characterization of ael Progranulin Deletion Associated with Different Phenotypes","volume":"76","author":"Picillo","year":"2020","journal-title":"J. Alzheimers Dis."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"277","DOI":"10.3233\/JAD-141380","article-title":"The novel GRN g.1159_1160delTG mutation is associated with behavioral variant frontotemporal dementia","volume":"44","author":"Calvi","year":"2015","journal-title":"J. Alzheimers Dis."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"e9","DOI":"10.1016\/j.neurobiolaging.2016.12.030","article-title":"GRN deletion in familial frontotemporal dementia showing association with clinical variability in 3 familial cases","volume":"53","author":"Milan","year":"2017","journal-title":"Neurobiol. Aging"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Taghdiri, F., Sato, C., Ghani, M., Moreno, D., Rogaeva, E., and Tartaglia, M.C. (2016). Novel GRN Mutations in Patients with Corticobasal Syndrome. Sci. Rep., 6.","DOI":"10.1038\/srep22913"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2506","DOI":"10.1016\/j.neurobiolaging.2011.10.031","article-title":"Granulin mutation drives brain damage and reorganization from preclinical to symptomatic FTLD","volume":"33","author":"Borroni","year":"2012","journal-title":"Neurobiol. Aging"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1002\/mds.22078","article-title":"Novel progranulin mutation: Screening for PGRN mutations in a Portuguese series of FTD\/CBS cases","volume":"23","author":"Guerreiro","year":"2008","journal-title":"Mov. Disord."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1159\/000510106","article-title":"Autosomal Dominant Frontotemporal Lobar Degeneration in a Filipino Family with Progranulin Mutation","volume":"49","author":"Dominguez","year":"2020","journal-title":"Dement. Geriatr. Cogn. Disord."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.3233\/JAD-160647","article-title":"Ael Loss-of-Function GRN Mutation p.(Tyr229*): Clinical and Neuropathological Features","volume":"55","author":"Kuuluvainen","year":"2017","journal-title":"J. Alzheimers Dis."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Natarajan, K., Eisfeldt, J., Hammond, M., Laffita-Mesa, J.M., Patra, K., Khoshnood, B., \u00d6ijerstedt, L., and Graff, C. (2021). Single-cell multimodal analysis in a case with reduced penetrance of Progranulin-Frontotemporal Dementia. Acta Neuropathol. Commun., 9.","DOI":"10.1186\/s40478-021-01234-2"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1038\/ejhg.2013.37","article-title":"el progranulin mutations with reduced serum-progranulin levels in frontotemporal lobar degeneration","volume":"21","author":"Chiang","year":"2013","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Benussi, A., Padovani, A., and Borroni, B. (2015). Phenotypic Heterogeneity of Monogenic Frontotemporal Dementia. Front. Aging Neurosci., 7.","DOI":"10.3389\/fnagi.2015.00171"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1016\/j.neurobiolaging.2015.11.026","article-title":"Progranulin mutation analysis: Identification of one novel mutation in exon 12 associated with frontotemporal dementia","volume":"39","author":"Aswathy","year":"2016","journal-title":"Neurobiol. Aging"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1002\/ana.20963","article-title":"HDDD2 is a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions caused by a missense mutation in the signal peptide of progranulin","volume":"60","author":"Mukherjee","year":"2006","journal-title":"Ann. Neurol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1016\/j.neurobiolaging.2015.10.029","article-title":"Missense mutations in progranulin gene associated with frontotemporal lobar degeneration: Study of pathogenetic features","volume":"38","author":"Karch","year":"2016","journal-title":"Neurobiol. Aging"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1016\/j.neurobiolaging.2017.02.008","article-title":"Missense mutation in GRN gene affecting RNA splicing and plasma progranulin level in a family affected by frontotemporal lobar degeneration","volume":"54","author":"Luzzi","year":"2017","journal-title":"Neurobiol. Aging"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"2195","DOI":"10.1515\/cclm-2023-0562","article-title":"Analytical and clinical validation of a blood progranulin ELISA in frontotemporal dementias","volume":"61","author":"Meda","year":"2023","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1093\/brain\/awn352","article-title":"Plasma progranulin levels predict progranulin mutation status in frontotemporal dementia patients and asymptomatic family members","volume":"132","author":"Finch","year":"2009","journal-title":"Brain"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1159\/000352022","article-title":"Progranulin peripheral levels as a screening tool for the identification of subjects with progranulin mutations in a Portuguese cohort","volume":"13","author":"Almeida","year":"2014","journal-title":"Neurodegener. Dis."},{"key":"ref_82","first-page":"180","article-title":"Circulating progranulin as a biomarker for neurodegenerative diseases","volume":"1","author":"Ghidoni","year":"2012","journal-title":"Am. J. Neurodegener. Dis."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1562","DOI":"10.1001\/jamaneurol.2014.1316","article-title":"Extensive white matter involvement in patients with frontotemporal lobar degeneration: Think progranulin","volume":"71","author":"Caroppo","year":"2014","journal-title":"JAMA Neurol."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Sung, W., Noh, M.Y., Nahm, M., Kim, Y.S., Ki, C.S., Kim, Y.E., Kim, H.J., and Kim, S.H. (2024). Progranulin haploinsufficiency mediates cytoplasmic TDP-43 aggregation with lysosomal abnormalities in human microglia. J. Neuroinflamm., 21.","DOI":"10.1186\/s12974-024-03039-1"},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Ljubenkov, P.A., Edwards, L., Iaccarino, L., La Joie, R., Rojas, J.C., Koestler, M., Harris, B., Boeve, B.F., Borroni, B., and van Swieten, J.C. (2021). Effect of the Histone Deacetylase Inhibitor FRM-0334 on Progranulin Levels in Patients With Progranulin Gene Haploinsufficiency: A Randomized Clinical Trial. JAMA Netw. Open, 4.","DOI":"10.1001\/jamanetworkopen.2021.25584"},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Ljubenkov, P.A., Miller, Z., Mumford, P., Zhang, J., Allen, I.E., Mitic, L., Staffaroni, A., Heuer, H., Rojas, J.C., and Cobigo, Y. (2019). Peripheral Innate Immune Activation Correlates With Disease Severity in GRN Haploinsufficiency. Front. Neurol., 10.","DOI":"10.3389\/fneur.2019.01004"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.3233\/JAD-170747","article-title":"Serum C-Peptide, Visfatin, Resistin, and Ghrelin are Altered in Sporadic and GRN-Associated Frontotemporal Lobar Degeneration","volume":"61","author":"Zanardini","year":"2018","journal-title":"J. Alzheimers Dis."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Arrant, A.E., Roth, J.R., Boyle, N.R., Kashyap, S.N., Hoffmann, M.Q., Murchison, C.F., Ramos, E.M., Nana, A.L., Spina, S., and Grinberg, L.T. (2019). Impaired \u03b2-glucocerebrosidase activity and processing in frontotemporal dementia due to progranulin mutations. Acta Neuropathol. Commun., 7.","DOI":"10.1186\/s40478-019-0872-6"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"4861","DOI":"10.1093\/hmg\/ddx364","article-title":"Progranulin-mediated deficiency of cathepsin D results in FTD and NCL-like phenotypes in neurons derived from FTD patients","volume":"26","author":"Valdez","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Zhou, X., Sun, L., Bracko, O., Choi, J.W., Jia, Y., Nana, A.L., Brady, O.A., Hernandez, J.C.C., Nishimura, N., and Seeley, W.W. (2017). Impaired prosaposin lysosomal trafficking in frontotemporal lobar degeneration due to progranulin mutations. Nat. Commun., 8.","DOI":"10.1038\/ncomms15277"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.stemcr.2014.12.001","article-title":"Restoration of progranulin expression rescues cortical neuron generation in an induced pluripotent stem cell model of frontotemporal dementia","volume":"4","author":"Raitano","year":"2015","journal-title":"Stem Cell Rep."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1016\/j.celrep.2012.09.007","article-title":"Induced pluripotent stem cell models of progranulin-deficient frontotemporal dementia uncover specific reversible neuronal defects","volume":"2","author":"Almeida","year":"2012","journal-title":"Cell Rep."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"16101","DOI":"10.1074\/jbc.M110.193433","article-title":"Suberoylanilide hydroxamic acid (vorinostat) up-regulates progranulin transcription: Rational therapeutic approach to frontotemporal dementia","volume":"286","author":"Cenik","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.neurobiolaging.2016.03.001","article-title":"Suberoylanilide hydroxamic acid increases progranulin production in iPSC-derived cortical neurons of frontotemporal dementia patients","volume":"42","author":"Almeida","year":"2016","journal-title":"Neurobiol. Aging"},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Oliveira, A.R., Martins, S., Cammarata, G., Martins, M., Cardoso, A.M., Almeida, M.R., do Carmo Mac\u00e1rio, M., Santana, I., Pe\u00e7a, J., and Cardoso, A.L. (2022). Generation and Characterization ofel iPSC Lines from a Portuguese Family Bearing Heterozygous and Homozygous GRN Mutations. Biomedicines, 10.","DOI":"10.3390\/biomedicines10081905"},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Holler, C.J., Taylor, G., Deng, Q., and Kukar, T. (2017). Intracellular Proteolysis of Progranulin Generates Stable, Lysosomal Granulins that Are Haploinsufficient in Patients with Frontotemporal Dementia Caused by GRN Mutations. eNeuro, 4.","DOI":"10.1523\/ENEURO.0100-17.2017"},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Ward, M.E., Chen, R., Huang, H.Y., Ludwig, C., Telpoukhovskaia, M., Taubes, A., Boudin, H., Minami, S.S., Reichert, M., and Albrecht, P. (2017). Individuals with progranulin haploinsufficiency exhibit features of neuronal ceroid lipofuscinosis. Sci. Transl. Med., 9.","DOI":"10.1126\/scitranslmed.aah5642"},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Boland, S., Swarup, S., Ambaw, Y.A., Malia, P.C., Richards, R.C., Fischer, A.W., Singh, S., Aggarwal, G., Spina, S., and Nana, A.L. (2022). Deficiency of the frontotemporal dementia gene GRN results in gangliosidosis. Nat. Commun., 13.","DOI":"10.1038\/s41467-022-33500-9"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1016\/j.neurobiolaging.2013.09.021","article-title":"PGRN haploinsufficiency increased Wnt5a signaling in peripheral cells from frontotemporal lobar degeneration-progranulin mutation carriers","volume":"35","author":"Esteras","year":"2014","journal-title":"Neurobiol. Aging"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1503\/jpn.150131","article-title":"Progranulin deficiency induces overactivation of WNT5A expression via TNF-\u03b1\/NF-\u03baB pathway in peripheral cells from frontotemporal dementia-linked granulin mutation carriers","volume":"41","author":"Moreno","year":"2016","journal-title":"J. Psychiatry Neurosci."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1093\/jnen\/nlz102","article-title":"Suppression of Progranulin Expression Leads to Formation of Intranuclear TDP-43 Inclusions In Vitro: A Cell Model of Frontotemporal Lobar Degeneration","volume":"78","author":"Zhu","year":"2019","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"5352","DOI":"10.1523\/JNEUROSCI.6103-11.2013","article-title":"Dissociation of frontotemporal dementia-related deficits and neuroinflammation in progranulin haploinsufficient mice","volume":"33","author":"Filiano","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1111\/gbb.12300","article-title":"Progranulin haploinsufficiency causes biphasic social dominance abnormalities in the tube test","volume":"15","author":"Arrant","year":"2016","journal-title":"Genes. Brain Behav."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Cook, A.K., Greathouse, K.M., Manuel, P.N., Cooper, N.H., Eberhardt, J.M., Freeman, C.D., Weber, A.J., Herskowitz, J.H., and Arrant, A.E. (2024). Dendritic spine head diameter is reduced in the prefrontal cortex of progranulin haploinsufficient mice. Mol. Brain, 17.","DOI":"10.1186\/s13041-024-01095-5"},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Life, B., Petkau, T.L., Cruz, G.N.F., Navarro-Delgado, E.I., Shen, N., Korthauer, K., and Leavitt, B.R. (2023). FTD-associated behavioural and transcriptomic abnormalities in \u2018humanized\u2019 progranulin-deficient mice: A novel model for progranulin-associated FTD. Neurobiol. Dis., 182.","DOI":"10.1016\/j.nbd.2023.106138"},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Frew, J., and Nygaard, H.B. (2021). Neuropathological and behavioral characterization of aged Grn R493X progranulin-deficient frontotemporal dementia knockin mice. Acta Neuropathol. Commun., 9.","DOI":"10.1186\/s40478-021-01158-x"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"9708","DOI":"10.1007\/s12035-024-04190-9","article-title":"Biochemical, Biomarker, and Behavioral Characterization of the GrnR493X Mouse Model of Frontotemporal Dementia","volume":"61","author":"Smith","year":"2024","journal-title":"Mol. Neurobiol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"E2849","DOI":"10.1073\/pnas.1722344115","article-title":"Murine knockin model for progranulin-deficient frontotemporal dementia with nonsense-mediated mRNA decay","volume":"115","author":"Nguyen","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Kaplelach, A.K., Fox, S.N., Cook, A.K., Hall, J.A., Dannemiller, R.S., Jaunarajs, K.L., and Arrant, A.E. (2023). Regulation of extracellular progranulin in medial prefrontal cortex. Neurobiol. Dis., 188.","DOI":"10.1016\/j.nbd.2023.106326"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1038\/nm.3672","article-title":"Progranulin protects against amyloid \u03b2 deposition and toxicity in Alzheimer\u2019s disease mouse models","volume":"20","author":"Minami","year":"2014","journal-title":"Nat. Med."},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Mendsaikhan, A., Tooyama, I., and Walker, D.G. (2019). Microglial Progranulin: Involvement in Alzheimer\u2019s Disease and Neurodegenerative Diseases. Cells, 8.","DOI":"10.3390\/cells8030230"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1538\/expanim.17-0060","article-title":"Progranulin haploinsufficiency reduces amyloid beta deposition in Alzheimer\u2019s disease model mice","volume":"67","author":"Hosokawa","year":"2018","journal-title":"Exp. Anim."},{"key":"ref_113","doi-asserted-by":"crossref","unstructured":"Arrant, A.E., Nicholson, A.M., Zhou, X., Rademakers, R., and Roberson, E.D. (2018). Partial Tmem106b reduction does not correct abnormalities due to progranulin haploinsufficiency. Mol. Neurodegener., 13.","DOI":"10.1186\/s13024-018-0264-6"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1097\/NEN.0000000000000158","article-title":"Progranulin reduction is associated with increased tau phosphorylation in P301L tau transgenic mice","volume":"74","author":"Hosokawa","year":"2015","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_115","doi-asserted-by":"crossref","unstructured":"Reifschneider, A., Robinson, S., van Lengerich, B., Gn\u00f6rich, J., Logan, T., Heindl, S., Vogt, M.A., Weidinger, E., Riedl, L., and Wind, K. (2022). Loss of TREM2 rescues hyperactivation of microglia, but not lysosomal deficits and neurotoxicity in models of progranulin deficiency. EMBO J., 41.","DOI":"10.15252\/embj.2021109108"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"11126","DOI":"10.1523\/JNEUROSCI.6244-10.2011","article-title":"Progranulin deficiency decreases gross neural connectivity but enhances transmission at individual synapses","volume":"31","author":"Tapia","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1124\/jpet.117.242164","article-title":"Depletion of Progranulin Reduces GluN2B-Containing NMDA Receptor Density, Tau Phosphorylation, and Dendritic Arborization in Mouse Primary Cortical Neurons","volume":"363","author":"Longhena","year":"2017","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1080\/14728222.2018.1487951","article-title":"Progranulin as a therapeutic target for dementia","volume":"22","author":"Galimberti","year":"2018","journal-title":"Expert. Opin. Ther. Targets"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1016\/j.neuron.2010.09.034","article-title":"Sortilin-mediated endocytosis determines levels of the frontotemporal dementia protein, progranulin","volume":"68","author":"Hu","year":"2010","journal-title":"Neuron"},{"key":"ref_120","doi-asserted-by":"crossref","unstructured":"Terryn, J., Verfaillie, C.M., and Van Damme, P. (2021). Tweaking Progranulin Expression: Therapeutic Avenues and Opportunities. Front. Mol. Neurosci., 14.","DOI":"10.3389\/fnmol.2021.713031"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"3081","DOI":"10.1093\/brain\/awx198","article-title":"Progranulin: A new avenue towards the understanding and treatment of neurodegenerative disease","volume":"140","author":"Chitramuthu","year":"2017","journal-title":"Brain"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1093\/brain\/awx060","article-title":"Restoring neuronal progranulin reverses deficits in a mouse model of frontotemporal dementia","volume":"140","author":"Arrant","year":"2017","journal-title":"Brain"},{"key":"ref_123","doi-asserted-by":"crossref","unstructured":"Nicholson, A.M., Gass, J., Petrucelli, L., and Rademakers, R. (2012). Progranulin axis and recent developments in frontotemporal lobar degeneration. Alzheimers Res. Ther., 4.","DOI":"10.1186\/alzrt102"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"1406","DOI":"10.1038\/s41591-024-02973-0","article-title":"Progranulin AAV gene therapy for frontotemporal dementia: Translational studies and phase 1\/2 trial interim results","volume":"30","author":"Sevigny","year":"2024","journal-title":"Nat. Med."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"2341","DOI":"10.1523\/JNEUROSCI.3081-17.2018","article-title":"Progranulin Gene Therapy Improves Lysosomal Dysfunction and Microglial Pathology Associated with Frontotemporal Dementia and Neuronal Ceroid Lipofuscinosis","volume":"38","author":"Arrant","year":"2018","journal-title":"J. Neurosci."},{"key":"ref_126","doi-asserted-by":"crossref","unstructured":"Banzhaf-Strathmann, J., Claus, R., M\u00fccke, O., Rentzsch, K., van der Zee, J., Engelborghs, S., De Deyn, P.P., Cruts, M., van Broeckhoven, C., and Plass, C. (2013). Promoter DNA methylation regulates progranulin expression and is altered in FTLD. Acta Neuropathol. Commun., 1.","DOI":"10.1186\/2051-5960-1-16"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"3769","DOI":"10.1021\/acschemneuro.9b00281","article-title":"Kinetic Tuning of HDAC Inhibitors Affords Potent Inducers of Progranulin Expression","volume":"10","author":"Fass","year":"2019","journal-title":"ACS Chem. Neurosci."},{"key":"ref_128","doi-asserted-by":"crossref","unstructured":"Rosenthal, Z.C., Fass, D.M., Payne, N.C., She, A., Patnaik, D., Hennig, K.M., Tesla, R., Werthmann, G.C., Guhl, C., and Reis, S.A. (2024). Epigenetic modulation through BET bromodomain inhibitors as a novel therapeutic strategy for progranulin-deficient frontotemporal dementia. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-59110-7"},{"key":"ref_129","doi-asserted-by":"crossref","unstructured":"Dabrowski, M., Bukowy-Bieryllo, Z., and Zietkiewicz, E. (2018). Advances in therapeutic use of a drug-stimulated translational readthrough of premature termination codons. Mol. Med., 24.","DOI":"10.1186\/s10020-018-0024-7"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"4677","DOI":"10.1007\/s00018-021-03809-7","article-title":"Nonsense suppression therapies in human genetic diseases","volume":"78","year":"2021","journal-title":"Cell Mol. Life Sci."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1111\/jnc.13640","article-title":"Therapy and clinical trials in frontotemporal dementia: Past, present, and future","volume":"138","author":"Tsai","year":"2016","journal-title":"J. Neurochem."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1007\/s10072-014-1683-y","article-title":"Results from a pilot study on amiodarone administration in monogenic frontotemporal dementia with granulin mutation","volume":"35","author":"Alberici","year":"2014","journal-title":"Neurol. Sci."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"1885","DOI":"10.1523\/JNEUROSCI.5757-10.2011","article-title":"Rescue of progranulin deficiency associated with frontotemporal lobar degeneration by alkalizing reagents and inhibition of vacuolar ATPase","volume":"31","author":"Capell","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_134","doi-asserted-by":"crossref","unstructured":"Holler, C.J., Taylor, G., McEachin, Z.T., Deng, Q., Watkins, W.J., Hudson, K., Easley, C.A., Hu, W.T., Hales, C.M., and Rossoll, W. (2016). Trehalose upregulates progranulin expression in human and mouse models of GRN haploinsufficiency: A novel therapeutic lead to treat frontotemporal dementia. Mol. Neurodegener., 11.","DOI":"10.1186\/s13024-016-0114-3"},{"key":"ref_135","doi-asserted-by":"crossref","unstructured":"Chen, A., and Gibney, P.A. (2023). Dietary Trehalose as a Bioactive Nutrient. Nutrients, 15.","DOI":"10.3390\/nu15061393"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1093\/hmg\/ddt534","article-title":"Targeted manipulation of the sortilin-progranulin axis rescues progranulin haploinsufficiency","volume":"23","author":"Lee","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_137","doi-asserted-by":"crossref","unstructured":"Miyakawa, S., Sakuma, H., Warude, D., Asanuma, S., Arimura, N., Yoshihara, T., Tavares, D., Hata, A., Ida, K., and Hori, Y. (2020). Anti-sortilin1 Antibody Up-Regulates Progranulin via Sortilin1 Down-Regulation. Front. Neurosci., 14.","DOI":"10.3389\/fnins.2020.586107"},{"key":"ref_138","doi-asserted-by":"crossref","unstructured":"G\u00f6tzl, J.K., Brendel, M., Werner, G., Parhizkar, S., Monasor, L.S., Kleinberger, G., Colombo, A., Deussing, M., Wagner, M., and Winkelmann, J. (2019). Opposite microglial activation stages upon loss of PGRN or TREM 2 result in reduced cerebral glucose metabolism. EMBO Mol. Med., 11.","DOI":"10.15252\/emmm.201809711"},{"key":"ref_139","doi-asserted-by":"crossref","unstructured":"Aggarwal, G., Banerjee, S., Jones, S.A., Benchaar, Y., B\u00e9langer, J., S\u00e9vigny, M., Smith, D.M., Niehoff, M.L., Pavlack, M., and de Vera, I.M.S. (2023). Antisense oligonucleotides targeting the miR-29b binding site in the GRN mRNA increase progranulin translation. J. Biol. Chem., 299.","DOI":"10.1016\/j.jbc.2023.105475"},{"key":"ref_140","doi-asserted-by":"crossref","unstructured":"Cao, Z., He, W., Hu, R., Chen, Y., Xue, J., Gao, F., and Lan, Y. (2025). Honokiol rescues progranulin deficiency in pathogen-induced and genetically driven neurodegeneration: Bridging veterinary models with therapeutic development. Vet. Microbiol., 307.","DOI":"10.1016\/j.vetmic.2025.110616"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1089\/ars.2009.2440","article-title":"Honokiol, a multifunctional antiangiogenic and antitumor agent","volume":"11","author":"Fried","year":"2009","journal-title":"Antioxid. Redox Signal."},{"key":"ref_142","doi-asserted-by":"crossref","unstructured":"Yao, X., Qin, R., Cui, Z., He, D., Sun, X., Sun, Y., and He, X. (2024). Effect of overexpression of GRN on the proliferation and osteogenic capacity of human periodontal cells. Exp. Ther. Med., 29.","DOI":"10.3892\/etm.2024.12783"},{"key":"ref_143","doi-asserted-by":"crossref","unstructured":"Kusakari, S., Suzuki, H., Nawa, M., Sudo, K., Yamazaki, R., Miyagi, T., Ohara, T., Matsuoka, M., and Kanekura, K. (2025). Excessive expression of progranulin leads to neurotoxicity rather than neuroprotection. Neurobiol. Dis., 209.","DOI":"10.1016\/j.nbd.2025.106895"},{"key":"ref_144","doi-asserted-by":"crossref","unstructured":"Huang, M., Modeste, E., Dammer, E., Merino, P., Taylor, G., Duong, D.M., Deng, Q., Holler, C.J., Gearing, M., and Dickson, D. (2020). Network analysis of the progranulin-deficient mouse brain proteome reveals pathogenic mechanisms shared in human frontotemporal dementia caused by GRN mutations. Acta Neuropathol. Commun., 8.","DOI":"10.1186\/s40478-020-01037-x"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.jns.2009.07.011","article-title":"Progranulin plasma levels as potential biomarker for the identification of GRN deletion carriers. A case with atypical onset as clinical amnestic Mild Cognitive Impairment converted to Alzheimer\u2019s disease","volume":"287","author":"Carecchio","year":"2009","journal-title":"J. Neurol. Sci."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1159\/000447738","article-title":"Progranulin Levels in Plasma and Cerebrospinal Fluid in Granulin Mutation Carriers","volume":"6","author":"Meeter","year":"2016","journal-title":"Dement. Geriatr. Cogn. Dis. Extra"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00401-018-1861-8","article-title":"The lysosomal function of progranulin, a guardian against neurodegeneration","volume":"136","author":"Paushter","year":"2018","journal-title":"Acta Neuropathol."},{"key":"ref_148","doi-asserted-by":"crossref","unstructured":"Gaweda-Walerych, K., Aragona, V., Lodato, S., Sitek, E.J., Naro\u017ca\u0144ska, E., and Buratti, E. (2025). Progranulin deficiency in the brain: The interplay between neuronal and non-neuronal cells. Transl. Neurodegener., 14.","DOI":"10.1186\/s40035-025-00475-8"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1038\/s42003-025-08272-9","article-title":"PGRN as an emerging regulator of lipid metabolism in neurodegenerative diseases","volume":"8","author":"Shi","year":"2025","journal-title":"Commun. Biol."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.bbr.2007.07.020","article-title":"Alteration of behavioural phenotype in mice by targeted disruption of the progranulin gene","volume":"185","author":"Kayasuga","year":"2007","journal-title":"Behav. Brain Res."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1084\/jem.20091568","article-title":"Exaggerated inflammation, impaired host defense, and neuropathology in progranulin-deficient mice","volume":"207","author":"Yin","year":"2010","journal-title":"J. Exp. Med."},{"key":"ref_152","first-page":"4639","article-title":"Behavioral deficits and progressive neuropathology in progranulin-deficient mice: A mouse model of frontotemporal dementia","volume":"24","author":"Yin","year":"2010","journal-title":"FASEB J."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1007\/s12035-012-8380-8","article-title":"Mechanisms of granulin deficiency: Lessons from cellular and animal models","volume":"47","author":"Kleinberger","year":"2013","journal-title":"Mol. Neurobiol."},{"key":"ref_154","doi-asserted-by":"crossref","unstructured":"Reich, M., Simon, M.J., Polke, B., Paris, I., Werner, G., Schrader, C., Spieth, L., Davis, S.S., Robinson, S., and de Melo, G.L. (2024). Peripheral expression of brain-penetrant progranulin rescues pathologies in mouse models of frontotemporal lobar degeneration. Sci. Transl. Med., 16.","DOI":"10.1126\/scitranslmed.adj7308"},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1007\/s13311-023-01348-6","article-title":"Preclinical Interventions in Mouse Models of Frontotemporal Dementia Due to Progranulin Mutations","volume":"20","author":"Kashyap","year":"2023","journal-title":"Neurotherapeutics"},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1007\/978-1-4939-8559-3_16","article-title":"Methods to Investigate the Molecular Basis of Progranulin Actions on Brain and Behavior In Vivo Using Knockout Mice","volume":"1806","author":"Boddaert","year":"2018","journal-title":"Methods Mol. Biol."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1016\/j.tips.2021.11.015","article-title":"Progranulin as a therapeutic target in neurodegenerative diseases","volume":"43","author":"Rhinn","year":"2022","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.cytogfr.2019.01.002","article-title":"Progranulin: A conductor of receptors orchestra, a chaperone of lysosomal enzymes and a therapeutic target for multiple diseases","volume":"45","author":"Cui","year":"2019","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_159","doi-asserted-by":"crossref","unstructured":"Boylan, M.A., Pincetic, A., Romano, G., Tatton, N., Kenkare-Mitra, S., and Rosenthal, A. (2023). Targeting Progranulin as an Immuno-Neurology Therapeutic Approach. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242115946"},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.brainres.2012.01.047","article-title":"Progranulin: An emerging target for FTLD therapies","volume":"1462","author":"Gass","year":"2012","journal-title":"Brain Res."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"32298","DOI":"10.1074\/jbc.R112.399170","article-title":"Progranulin: A proteolytically processed protein at the crossroads of inflammation and neurodegeneration","volume":"287","author":"Cenik","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_162","doi-asserted-by":"crossref","unstructured":"Elia, L.P., Reisine, T., Alijagic, A., and Finkbeiner, S. (2020). Approaches to develop therapeutics to treat frontotemporal dementia. Neuropharmacology, 166.","DOI":"10.1016\/j.neuropharm.2020.107948"},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.jalz.2012.03.002","article-title":"Frontotemporal degeneration, the next therapeutic frontier: Molecules and animal models for frontotemporal degeneration drug development","volume":"9","author":"Boxer","year":"2012","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_164","doi-asserted-by":"crossref","unstructured":"Root, J., Mendsaikhan, A., Taylor, G., Merino, P., Nandy, S., Wang, M., Araujo, L.T., Ryu, D., Holler, C., and Thompson, B.M. (2024). Granulins rescue inflammation, lysosome dysfunction, lipofuscin, and neuropathology in a mouse model of progranulin deficiency. Cell Rep., 43.","DOI":"10.1016\/j.celrep.2024.114985"},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1080\/13543784.2024.2349286","article-title":"Frontotemporal dementia: From genetics to therapeutic approaches","volume":"33","author":"Buccellato","year":"2024","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1016\/j.tcb.2022.09.006","article-title":"Lysosomal functions of progranulin and implications for treatment of frontotemporal dementia","volume":"33","author":"Simon","year":"2022","journal-title":"Trends Cell Biol."},{"key":"ref_167","unstructured":"(2025, September 30). Available online: http:\/\/clinicaltrials.eu\/trial\/study-on-avb-101-for-patients-with-frontotemporal-dementia-with-progranulin-mutations\/."},{"key":"ref_168","unstructured":"(2025, September 30). Available online: https:\/\/www.clinicaltrials.gov\/study\/NCT04747431?tab=table#trial-description."},{"key":"ref_169","unstructured":"(2025, September 30). Available online: https:\/\/www.clinicaltrials.gov\/study\/NCT04747431."},{"key":"ref_170","unstructured":"Voss, T., Triglia, P., Ni, Y.G., Browne, S.E., Chou, W., Ducharme, S., Irwin, D.J., and Santana, I. (2025, September 30). Interim Safety and Biomarker Data From upliFT-D Trial of PBFT02 in FTD with GRN Mutations, Alzheimer\u2019s Association International Conference (AAIC). Available online: https:\/\/s203.q4cdn.com\/877117837\/files\/doc_events\/2025\/Jul\/30\/Passage-Bio_AAIC-2025_UPLIFT-D-Poster-114x114cm-S03-DIGITAL.pdf."},{"key":"ref_171","doi-asserted-by":"crossref","unstructured":"Wang, C., Pan, C., Yong, H., Wang, F., Bo, T., Zhao, Y., Ma, B., He, W., and Li, M. (2023). Emerging non-viral vectors for gene delivery. J. Nanobiotechnol., 21.","DOI":"10.1186\/s12951-023-02044-5"},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"11357","DOI":"10.2147\/IJN.S484838","article-title":"Nanoparticle-Based Drug Delivery Systems Enhance Treatment of Cognitive Defects","volume":"19","author":"Wilar","year":"2024","journal-title":"Int. J. Nanomed."},{"key":"ref_173","doi-asserted-by":"crossref","unstructured":"Yan, D., Ouyang, W., Lin, J., and Liu, Z. (2023). Smart coating by thermo-sensitive Pluronic F-127 for enhanced corneal healing via delivery of biological macromolecule progranulin. Int. J. Biol. Macromol., 253.","DOI":"10.1016\/j.ijbiomac.2023.127586"},{"key":"ref_174","doi-asserted-by":"crossref","unstructured":"Tesla, R., Guhl, C., Werthmann, G.C., Dixon, D., Cenik, B., Addepalli, Y., Liang, J., Fass, D.M., Rosenthal, Z., and Haggarty, S.J. (2024). Benzoxazole-derivatives enhance progranulin expression and reverse the aberrant lysosomal proteome caused by GRN haploinsufficiency. Nat. Commun., 15.","DOI":"10.1038\/s41467-024-50076-8"},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"715","DOI":"10.3233\/JAD-220883","article-title":"First-In-Human Safety, Tolerability, and Pharmacokinetics of Single and Multiple Doses of AZP2006, A Synthetic Compound for the Treatment of Alzheimer\u2019s Disease and Related Diseases","volume":"98","author":"Verwaerde","year":"2024","journal-title":"J. Alzheimers Dis."},{"key":"ref_176","doi-asserted-by":"crossref","unstructured":"Callizot, N., Estrella, C., Burlet, S., Henriques, A., Brantis, C., Barrier, M., Campanari, M.L., and Verwaerde, P. (2021). AZP2006, a new promising treatment for Alzheimer\u2019s and related diseases. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-94708-1"},{"key":"ref_177","doi-asserted-by":"crossref","unstructured":"Kurnellas, M., Mitra, A., Schwabe, T., Paul, R., Arrant, A.E., Roberson, E.D., Ward, M., Yeh, F., Long, H., and Rosenthal, A. (2023). Latozinemab, a novel progranulin-elevating therapy for frontotemporal dementia. J. Transl. Med., 21.","DOI":"10.1186\/s12967-023-04251-y"},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"5335","DOI":"10.2147\/IJN.S455574","article-title":"Recent Updates of the CRISPR\/Cas9 Genome Editing System:el Approaches to Regulate Its Spatiotemporal Control by Genetic and Physicochemical Strategies","volume":"19","author":"Allemailem","year":"2024","journal-title":"Int. J. Nanomed."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1111\/j.1469-8749.1985.tb14135.x","article-title":"The effects of sex, birth order and admission to a special care baby unit on the fear of strangers reaction of infants","volume":"27","author":"Garrow","year":"1985","journal-title":"Dev. Med. Child. Neurol."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1055\/s-0044-1791803","article-title":"The Role of CRISPR\/Cas9 in Revolutionizing Duchenne\u2019s Muscular Dystrophy Treatment: Opportunities and Obstacles","volume":"11","author":"Ali","year":"2024","journal-title":"Glob. Med. Genet."},{"key":"ref_181","doi-asserted-by":"crossref","unstructured":"Yun, Y., and Ha, Y. (2020). CRISPR\/Cas9-Mediated Gene Correction to Understand ALS. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21113801"},{"key":"ref_182","doi-asserted-by":"crossref","unstructured":"Kim, H., Han, J.H., Kim, H., Kim, M., Jo, S.I., Lee, N., Cha, S., Oh, M.J., Choi, G., and Kim, H.S. (2024). CRISPR\/Cas9 targeting of passenger single nucleotide variants in haploinsufficient or essential genes expands cancer therapy prospects. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-58094-8"},{"key":"ref_183","doi-asserted-by":"crossref","unstructured":"Matharu, N., Rattanasopha, S., Tamura, S., Maliskova, L., Wang, Y., Bernard, A., Hardin, A., Eckalbar, W.L., Vaisse, C., and Ahituv, N. (2019). CRISPR-mediated activation of a promoter or enhancer rescues obesity caused by haploinsufficiency. Science, 363.","DOI":"10.1126\/science.aau0629"},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.1007\/s12640-022-00564-w","article-title":"CRISPR and iPSCs: Recent Developments and Future Perspectives in Neurodegenerative Disease Modelling, Research, and Therapeutics","volume":"40","author":"Sen","year":"2022","journal-title":"Neurotox. Res."},{"key":"ref_185","doi-asserted-by":"crossref","unstructured":"Raffaele, I., Cipriano, G.L., Anchesi, I., Oddo, S., and Silvestro, S. (2025). CRISPR\/Cas9 and iPSC-Based Therapeutic Approaches in Alzheimer\u2019s Disease. Antioxidants, 14.","DOI":"10.3390\/antiox14070781"},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.jalz.2019.06.4956","article-title":"New directions in clinical trials for frontotemporal lobar degeneration: Methods and outcome measures","volume":"16","author":"Boxer","year":"2020","journal-title":"Alzheimers Dement."},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"e9","DOI":"10.1016\/j.neurobiolaging.2017.10.016","article-title":"Progranulin plasma levels predict the presence of GRN mutations in asymptomatic subjects and do not correlate with brain atrophy: Results from the GENFI study","volume":"62","author":"Galimberti","year":"2018","journal-title":"Neurobiol. Aging"},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1080\/21678421.2020.1779302","article-title":"Variability of clinical syndromes and cerebral glucose metabolism in symptomatic frontotemporal lobar degeneration associated with progranulin mutations","volume":"21","author":"Licata","year":"2020","journal-title":"Amyotroph. Lateral Scler. Front. Degener."},{"key":"ref_189","doi-asserted-by":"crossref","unstructured":"Ferrari, R., Forabosco, P., Vandrovcova, J., Bot\u00eda, J.A., Guelfi, S., Warren, J.D., UK Brain Expression Consortium (UKBEC), Momeni, P., Weale, M.E., and Ryten, M. (2016). Frontotemporal dementia: Insights into the biological underpinnings of disease through gene co-expression network analysis. Mol. Neurodegener., 11.","DOI":"10.1186\/s13024-016-0085-4"},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1016\/S1474-4422(18)30126-1","article-title":"Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: A genome-wide association study","volume":"17","author":"Pottier","year":"2018","journal-title":"Lancet Neurol."},{"key":"ref_191","unstructured":"Motulsky, A.G., Holtzman, N.A., Fullarton, J.E., and Andrews, L.B. (2025, September 30). Social, Legal, and Ethical Implications of Genetic Testing, Assessing Genetic Risks: Implications for Health and Social Policy, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK236044\/."},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1080\/15265161.2013.828528","article-title":"What does the duty to warn require?","volume":"13","author":"Shah","year":"2013","journal-title":"Am. J. Bioeth."},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1080\/15390940903041583","article-title":"Ethical considerations of genetic presymptomatic testing for Huntington\u2019s disease","volume":"19","author":"Coustasse","year":"2009","journal-title":"J. Hosp. Mark. Public Relations"},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1089\/hum.2020.156","article-title":"Aspects of Gene Therapy Products Using Current Genome-Editing Technology in Japan","volume":"31","author":"Yamaguchi","year":"2020","journal-title":"Hum. Gene Ther."},{"key":"ref_195","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.neurobiolaging.2018.12.018","article-title":"Clinical and biomarker changes in presymptomatic genetic frontotemporal dementia","volume":"76","author":"Benussi","year":"2019","journal-title":"Neurobiol. Aging"},{"key":"ref_196","first-page":"474","article-title":"Human Genetics: Choice and Responsibility","volume":"62","author":"Wertz","year":"1998","journal-title":"Am. J. Hum. Genet."},{"key":"ref_197","doi-asserted-by":"crossref","unstructured":"Gee, M.S., Kwon, E., Song, M.H., Jeon, S.H., Kim, N., Lee, J.K., and Koo, T. (2024). CRISPR base editing-mediated correction of a tau mutation rescues cognitive decline in a mouse model of tauopathy. Transl. Neurodegener., 13.","DOI":"10.1186\/s40035-024-00415-y"},{"key":"ref_198","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.reth.2025.07.009","article-title":"CRISPR\/Cas9 a genomic engineering technology for treatment in ALS mouse models","volume":"30","author":"Khan","year":"2025","journal-title":"Regen. Ther."},{"key":"ref_199","doi-asserted-by":"crossref","unstructured":"Kempthorne, L., Vaizoglu, D., Cammack, A.J., Carcol\u00e9, M., Roberts, M.J., Mikheenko, A., Fisher, A., Suklai, P., Muralidharan, B., and Kroll, F. (2025). Dual-targeting CRISPR-CasRx reduces C9orf72 ALS\/FTD sense and antisense repeat RNAs in vitro and in vivo. Nat. Commun., 16.","DOI":"10.1038\/s41467-024-55550-x"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/20\/9960\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,18]],"date-time":"2025-10-18T04:24:36Z","timestamp":1760761476000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/20\/9960"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,13]]},"references-count":199,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["ijms26209960"],"URL":"https:\/\/doi.org\/10.3390\/ijms26209960","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,13]]}}}