{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T15:37:58Z","timestamp":1787067478547,"version":"build-2736575974"},"reference-count":201,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2023,11,3]],"date-time":"2023-11-03T00:00:00Z","timestamp":1698969600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Alector, Inc."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Immuno-neurology is an emerging therapeutic strategy for dementia and neurodegeneration designed to address immune surveillance failure in the brain. Microglia, as central nervous system (CNS)-resident myeloid cells, routinely perform surveillance of the brain and support neuronal function. Loss-of-function (LOF) mutations causing decreased levels of progranulin (PGRN), an immune regulatory protein, lead to dysfunctional microglia and are associated with multiple neurodegenerative diseases, including frontotemporal dementia caused by the progranulin gene (GRN) mutation (FTD-GRN), Alzheimer\u2019s disease (AD), Parkinson\u2019s disease (PD), limbic-predominant age-related transactivation response deoxyribonucleic acid binding protein 43 (TDP-43) encephalopathy (LATE), and amyotrophic lateral sclerosis (ALS). Immuno-neurology targets immune checkpoint-like proteins, offering the potential to convert aging and dysfunctional microglia into disease-fighting cells that counteract multiple disease pathologies, clear misfolded proteins and debris, promote myelin and synapse repair, optimize neuronal function, support astrocytes and oligodendrocytes, and maintain brain vasculature. Several clinical trials are underway to elevate PGRN levels as one strategy to modulate the function of microglia and counteract neurodegenerative changes associated with various disease states. If successful, these and other immuno-neurology drugs have the potential to revolutionize the treatment of neurodegenerative disorders by harnessing the brain\u2019s immune system and shifting it from an inflammatory\/pathological state to an enhanced physiological\/homeostatic state.<\/jats:p>","DOI":"10.3390\/ijms242115946","type":"journal-article","created":{"date-parts":[[2023,11,3]],"date-time":"2023-11-03T10:51:28Z","timestamp":1699008688000},"page":"15946","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Targeting Progranulin as an Immuno-Neurology Therapeutic Approach"],"prefix":"10.3390","volume":"24","author":[{"given":"Maria A.","family":"Boylan","sequence":"first","affiliation":[{"name":"Alector, Inc., 131 Oyster Point Blvd, Suite 600, South San Francisco, CA 94080, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Pincetic","sequence":"additional","affiliation":[{"name":"Alector, Inc., 131 Oyster Point Blvd, Suite 600, South San Francisco, CA 94080, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary","family":"Romano","sequence":"additional","affiliation":[{"name":"Alector, Inc., 131 Oyster Point Blvd, Suite 600, South San Francisco, CA 94080, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9576-8837","authenticated-orcid":false,"given":"Nadine","family":"Tatton","sequence":"additional","affiliation":[{"name":"Alector, Inc., 131 Oyster Point Blvd, Suite 600, South San Francisco, CA 94080, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Kenkare-Mitra","sequence":"additional","affiliation":[{"name":"Alector, Inc., 131 Oyster Point Blvd, Suite 600, South San Francisco, CA 94080, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnon","family":"Rosenthal","sequence":"additional","affiliation":[{"name":"Alector, Inc., 131 Oyster Point Blvd, Suite 600, South San Francisco, CA 94080, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1016\/0896-6273(91)90052-2","article-title":"The molecular pathology of Alzheimer\u2019s disease","volume":"6","author":"Selkoe","year":"1991","journal-title":"Neuron"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.jalz.2018.02.018","article-title":"NIA-AA research framework: Toward a biological definition of Alzheimer\u2019s disease","volume":"14","author":"Jack","year":"2018","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.neuron.2006.09.026","article-title":"Mechanisms of Parkinson\u2019s disease linked to pathological alpha-synuclein: New targets for drug discovery","volume":"52","author":"Lee","year":"2006","journal-title":"Neuron"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.tig.2004.01.008","article-title":"Huntingtin-protein interactions and the pathogenesis of Huntington\u2019s disease","volume":"20","author":"Li","year":"2004","journal-title":"Trends Genet."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Riku, Y., Yoshida, M., Iwasaki, Y., Sobue, G., Katsuno, M., and Ishigaki, S. (2022). TDP-43 proteinopathy and tauopathy: Do they have pathomechanistic links?. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232415755"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Mol, M.O., Miedema, S.S.M., van Swieten, J.C., van Rooij, J.G.J., and Dopper, E.G.P. (2021). Molecular pathways involved in frontotemporal lobar degeneration with TDP-43 proteinopathy: What can we learn from proteomics?. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms221910298"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1126\/science.1134108","article-title":"Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis","volume":"314","author":"Neumann","year":"2006","journal-title":"Science"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1177\/1073858414561795","article-title":"SOD1 function and its implications for amyotrophic lateral sclerosis pathology: New and renascent themes","volume":"21","author":"Saccon","year":"2015","journal-title":"Neuroscientist"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1136\/jnnp.2010.212225","article-title":"Clinical, genetic and pathological heterogeneity of frontotemporal dementia: A review","volume":"82","author":"Seelaar","year":"2011","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_10","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_11","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1056\/NEJMoa2212948","article-title":"Lecanemab in early Alzheimer\u2019s disease","volume":"388","author":"Swanson","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.1056\/NEJMoa2100708","article-title":"Donanemab in early Alzheimer\u2019s disease","volume":"384","author":"Mintun","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_13","first-page":"197","article-title":"Two randomized phase 3 studies of aducanumab in early Alzheimer\u2019s disease","volume":"9","author":"Aisen","year":"2022","journal-title":"J. Prev. Alzheimer\u2019s Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1038\/s41591-023-02326-3","article-title":"Tau-targeting antisense oligonucleotide MAPT(Rx) in mild Alzheimer\u2019s disease: A phase 1b, randomized, placebo-controlled trial","volume":"29","author":"Mummery","year":"2023","journal-title":"Nat. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1056\/NEJMoa2202867","article-title":"Trial of prasinezumab in early-stage Parkinson\u2019s disease","volume":"387","author":"Pagano","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2307","DOI":"10.1056\/NEJMoa1900907","article-title":"Targeting Huntingtin expression in patients with Huntington\u2019s disease","volume":"380","author":"Tabrizi","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1007\/s13311-022-01247-2","article-title":"Antisense oligonucleotides for the study and treatment of ALS","volume":"19","author":"Boros","year":"2022","journal-title":"Neurotherapeutics"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3345","DOI":"10.1016\/j.ymthe.2021.04.008","article-title":"Gene therapy for ALS: A review","volume":"29","author":"Amado","year":"2021","journal-title":"Mol. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1056\/NEJMoa2204705","article-title":"Trial of antisense oligonucleotide tofersen for SOD1 ALS","volume":"387","author":"Miller","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1007\/s13311-022-01260-5","article-title":"Emerging therapies and novel targets for TDP-43 proteinopathy in ALS\/FTD","volume":"19","author":"Hayes","year":"2022","journal-title":"Neurotherapeutics"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Dong, Y., Li, X., Cheng, J., and Hou, L. (2019). Drug development for Alzheimer\u2019s disease: Microglia induced neuroinflammation as a target?. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20030558"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"840","DOI":"10.3389\/fphar.2019.00840","article-title":"Microglial drug targets in AD: Opportunities and challenges in drug discovery and development","volume":"10","author":"Biber","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Qiao, O., Ji, H., Zhang, Y., Zhang, X., Zhang, X., Liu, N., Huang, L., Liu, C., and Gao, W. (2021). New insights in drug development for Alzheimer\u2019s disease based on microglia function. Biomed. Pharmacother., 140.","DOI":"10.1016\/j.biopha.2021.111703"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1314","DOI":"10.1126\/science.1110647","article-title":"Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo","volume":"308","author":"Nimmerjahn","year":"2005","journal-title":"Science"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1146\/annurev-immunol-051116-052358","article-title":"Microglia function in the central nervous system during health and neurodegeneration","volume":"35","author":"Colonna","year":"2017","journal-title":"Annu. Rev. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5816","DOI":"10.1038\/s41467-019-13812-z","article-title":"Dual microglia effects on blood brain barrier permeability induced by systemic inflammation","volume":"10","author":"Haruwaka","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1093\/jb\/mvw009","article-title":"Microglia in central nervous system repair after injury","volume":"159","author":"Jin","year":"2016","journal-title":"J. Biochem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1637","DOI":"10.1002\/glia.23961","article-title":"How microglia sense and regulate neuronal activity","volume":"69","author":"Umpierre","year":"2021","journal-title":"Glia"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"eabk1131","DOI":"10.1126\/sciadv.abk1131","article-title":"Regulation of myelination by microglia","volume":"7","author":"Santos","year":"2021","journal-title":"Sci. Adv."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.3389\/fimmu.2020.01024","article-title":"Interaction of microglia and astrocytes in the neurovascular unit","volume":"11","author":"Liu","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1111\/acel.12149","article-title":"Homeostatic and injury-induced microglia behavior in the aging brain","volume":"13","author":"Hefendehl","year":"2014","journal-title":"Aging Cell"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Greenwood, E.K., and Brown, D.R. (2021). Senescent microglia: The key to the ageing brain?. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22094402"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1016\/j.tins.2020.10.002","article-title":"Microglial phagocytosis: A disease-associated process emerging from Alzheimer\u2019s disease genetics","volume":"43","author":"Marcora","year":"2020","journal-title":"Trends Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1610","DOI":"10.1038\/s41467-021-21823-y","article-title":"Integration of Alzheimer\u2019s disease genetics and myeloid genomics identifies disease risk regulatory elements and genes","volume":"12","author":"Novikova","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.1126\/science.aay0793","article-title":"Brain cell type-specific enhancer-promoter interactome maps and disease-risk association","volume":"366","author":"Nott","year":"2019","journal-title":"Science"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1007\/s12035-010-8106-8","article-title":"Microglia activation and anti-inflammatory regulation in Alzheimer\u2019s disease","volume":"41","author":"Lue","year":"2010","journal-title":"Mol. Neurobiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.pharmthera.2013.04.013","article-title":"Microglia during development and aging","volume":"139","author":"Harry","year":"2013","journal-title":"Pharmacol. Ther."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.expneurol.2010.11.014","article-title":"Dysregulated neuronal-microglial cross-talk during aging, stress and inflammation","volume":"233","author":"Jurgens","year":"2012","journal-title":"Exp. Neurol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/nature21029","article-title":"Neurotoxic reactive astrocytes are induced by activated microglia","volume":"541","author":"Liddelow","year":"2017","journal-title":"Nature"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1007\/s00018-023-04775-y","article-title":"Aging microglia","volume":"80","author":"Antignano","year":"2023","journal-title":"Cell Mol. Life Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"NS20210008","DOI":"10.1042\/NS20210008","article-title":"Oligodendrocytes in the aging brain","volume":"5","author":"Sams","year":"2021","journal-title":"Neuronal Signal"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1038\/npp.2016.185","article-title":"Microglia priming with aging and stress","volume":"42","author":"Niraula","year":"2017","journal-title":"Neuropsychopharmacology"},{"key":"ref_43","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_44","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_45","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":"2023","journal-title":"Trends Cell Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1186\/s13024-018-0288-y","article-title":"Progranulin reduces insoluble TDP-43 levels, slows down axonal degeneration and prolongs survival in mutant TDP-43 mice","volume":"13","author":"Beel","year":"2018","journal-title":"Mol. Neurodegener."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1007\/s13238-010-0067-1","article-title":"Progranulin promotes neurite outgrowth and neuronal differentiation by regulating GSK-3beta","volume":"1","author":"Gao","year":"2010","journal-title":"Protein Cell"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/1750-1326-7-33","article-title":"Progranulin regulates neuronal outgrowth independent of sortilin","volume":"7","author":"Gass","year":"2012","journal-title":"Mol. Neurodegener."},{"key":"ref_49","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_50","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1083\/jcb.200712039","article-title":"Progranulin functions as a neurotrophic factor to regulate neurite outgrowth and enhance neuronal survival","volume":"181","author":"Lambrechts","year":"2008","journal-title":"J. Cell Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"8677","DOI":"10.1093\/nar\/gkr593","article-title":"Transcriptional gene network inference from a massive dataset elucidates transcriptome organization and gene function","volume":"39","author":"Belcastro","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1126\/science.1174447","article-title":"A gene network regulating lysosomal biogenesis and function","volume":"325","author":"Sardiello","year":"2009","journal-title":"Science"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.neuroscience.2013.06.049","article-title":"Increased lysosomal biogenesis in activated microglia and exacerbated neuronal damage after traumatic brain injury in progranulin-deficient mice","volume":"250","author":"Tanaka","year":"2013","journal-title":"Neuroscience"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1038\/nature05016","article-title":"Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17","volume":"442","author":"Baker","year":"2006","journal-title":"Nature"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1007\/s00401-007-0223-8","article-title":"The neuropathology and clinical phenotype of FTD with progranulin mutations","volume":"114","author":"Mackenzie","year":"2007","journal-title":"Acta Neuropathol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1016\/j.cell.2016.04.001","article-title":"Progranulin deficiency promotes circuit-specific synaptic pruning by microglia via complement activation","volume":"165","author":"Lui","year":"2016","journal-title":"Cell"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1038\/s41586-020-2709-7","article-title":"Neurotoxic microglia promote TDP-43 proteinopathy in progranulin deficiency","volume":"588","author":"Zhang","year":"2020","journal-title":"Nature"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1002\/ana.26032","article-title":"Heritability enrichment implicates microglia in Parkinson\u2019s disease pathogenesis","volume":"89","author":"Andersen","year":"2021","journal-title":"Ann. Neurol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"eaav7188","DOI":"10.1126\/science.aav7188","article-title":"Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility","volume":"365","year":"2019","journal-title":"Science"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"10042","DOI":"10.1038\/srep10042","article-title":"Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia caused by a novel R782G mutation in CSF1R","volume":"5","author":"Foulds","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Broce, I., Karch, C.M., Wen, N., Fan, C.C., Wang, Y., Tan, C.H., Kouri, N., Ross, O.A., Hoglinger, G.U., and Muller, U. (2018). Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies. PLoS Med., 15.","DOI":"10.1371\/journal.pmed.1002487"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1007\/s00401-019-01962-9","article-title":"Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD","volume":"137","author":"Pottier","year":"2019","journal-title":"Acta Neuropathol."},{"key":"ref_63","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_64","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1038\/s41588-022-01024-z","article-title":"New insights into the genetic etiology of alzheimer\u2019s disease and related dementias","volume":"54","author":"Bellenguez","year":"2022","journal-title":"Nat. Genet."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1038\/nri.2017.125","article-title":"Microglia and macrophages in brain homeostasis and disease","volume":"18","author":"Li","year":"2018","journal-title":"Nat. Rev. Immunol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1186\/s12974-021-02309-6","article-title":"The semantics of microglia activation: Neuroinflammation, homeostasis, and stress","volume":"18","author":"Woodburn","year":"2021","journal-title":"J. Neuroinflamm."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.tins.2020.01.003","article-title":"Astrocytes and microglia: In sickness and in health","volume":"43","author":"Vainchtein","year":"2020","journal-title":"Trends Neurosci."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Schwabe, T., Srinivasan, K., and Rhinn, H. (2020). Shifting paradigms: The central role of microglia in Alzheimer\u2019s disease. Neurobiol. Dis., 143.","DOI":"10.1016\/j.nbd.2020.104962"},{"key":"ref_69","first-page":"792","article-title":"An early and late peak in microglial activation in Alzheimer\u2019s disease trajectory","volume":"140","author":"Fan","year":"2017","journal-title":"Brain"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.4103\/1673-5374.272571","article-title":"Shifting equilibriums in Alzheimer\u2019s disease: The complex roles of microglia in neuroinflammation, neuronal survival and neurogenesis","volume":"15","author":"Gray","year":"2020","journal-title":"Neural Regen. Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1186\/1742-2094-9-155","article-title":"Neuroimmune crosstalk in the central nervous system and its significance for neurological diseases","volume":"9","author":"Tian","year":"2012","journal-title":"J. Neuroinflamm."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1038\/nm.3672","article-title":"Progranulin protects against amyloid beta deposition and toxicity in Alzheimer\u2019s disease mouse models","volume":"20","author":"Minami","year":"2014","journal-title":"Nat. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"3221","DOI":"10.1093\/brain\/awad078","article-title":"Microglial activation in the frontal cortex predicts cognitive decline in frontotemporal dementia","volume":"146","author":"Malpetti","year":"2023","journal-title":"Brain"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1002\/ana.20332","article-title":"In vivo detection of microglial activation in frontotemporal dementia","volume":"56","author":"Cagnin","year":"2004","journal-title":"Ann. Neurol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1093\/brain\/awaa033","article-title":"Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum","volume":"143","author":"Cope","year":"2020","journal-title":"Brain"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1588","DOI":"10.1093\/brain\/awaa088","article-title":"Microglial activation and tau burden predict cognitive decline in Alzheimer\u2019s disease","volume":"143","author":"Malpetti","year":"2020","journal-title":"Brain"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1111\/nan.12092","article-title":"Patterns of microglial cell activation in frontotemporal lobar degeneration","volume":"40","author":"Lant","year":"2014","journal-title":"Neuropathol Appl. Neurobiol"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1186\/s12974-020-01907-0","article-title":"Microglial burden, activation and dystrophy patterns in frontotemporal lobar degeneration","volume":"17","author":"Woollacott","year":"2020","journal-title":"J. Neuroinflamm."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1782","DOI":"10.1002\/acn3.50875","article-title":"Microglia in frontotemporal lobar degeneration with progranulin or C9ORF72 mutations","volume":"6","author":"Sakae","year":"2019","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1584","DOI":"10.1038\/nn.4132","article-title":"Depletion of microglia and inhibition of exosome synthesis halt tau propagation","volume":"18","author":"Asai","year":"2015","journal-title":"Nat. Neurosci."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1038\/s41593-018-0242-x","article-title":"Microglia in neurodegeneration","volume":"21","author":"Hickman","year":"2018","journal-title":"Nat. Neurosci."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1186\/s12974-023-02853-3","article-title":"Tau and neuroinflammation in Alzheimer\u2019s disease: Interplay mechanisms and clinical translation","volume":"20","author":"Chen","year":"2023","journal-title":"J. Neuroinflamm."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1738","DOI":"10.1093\/brain\/awv081","article-title":"Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain","volume":"138","author":"Maphis","year":"2015","journal-title":"Brain"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1774","DOI":"10.1126\/science.1197623","article-title":"Decreased clearance of CNS beta-amyloid in Alzheimer\u2019s disease","volume":"330","author":"Mawuenyega","year":"2010","journal-title":"Science"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1136\/jnnp.74.9.1200","article-title":"Intrathecal inflammation precedes development of Alzheimer\u2019s disease","volume":"74","author":"Tarkowski","year":"2003","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"307","DOI":"10.3109\/00207454.2013.833510","article-title":"Microglia, neuroinflammation, and beta-amyloid protein in Alzheimer\u2019s disease","volume":"124","author":"Cai","year":"2014","journal-title":"Int. J. Neurosci."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/s40035-015-0041-1","article-title":"The endosomal-lysosomal system: From acidification and cargo sorting to neurodegeneration","volume":"4","author":"Hu","year":"2015","journal-title":"Transl. Neurodegener."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.tins.2013.11.006","article-title":"Stuck in traffic: An emerging theme in diseases of the nervous system","volume":"37","author":"Neefjes","year":"2014","journal-title":"Trends Neurosci."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"E3699","DOI":"10.1073\/pnas.1510329112","article-title":"Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer\u2019s disease amyloid plaques","volume":"112","author":"Gowrishankar","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_90","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_91","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1038\/s41588-019-0358-2","article-title":"Genetic meta-analysis of diagnosed Alzheimer\u2019s disease identifies new risk loci and implicates Abeta, tau, immunity and lipid processing","volume":"51","author":"Kunkle","year":"2019","journal-title":"Nat. Genet."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1038\/ng.3916","article-title":"Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer\u2019s disease","volume":"49","author":"Sims","year":"2017","journal-title":"Nat. Genet."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1002\/ajmg.b.32499","article-title":"Genomic variants, genes, and pathways of Alzheimer\u2019s disease: An overview","volume":"174","author":"Naj","year":"2017","journal-title":"Am. J. Med. Genet. B Neuropsychiatr. Genet."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1038\/ng.801","article-title":"Common variants at MS4A4\/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer\u2019s disease","volume":"43","author":"Naj","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.neuron.2015.11.013","article-title":"Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse","volume":"89","author":"Zhang","year":"2016","journal-title":"Neuron"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"eaau2291","DOI":"10.1126\/scitranslmed.aau2291","article-title":"The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer\u2019s disease risk","volume":"11","author":"Deming","year":"2019","journal-title":"Sci. Transl. Med."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"eaav6221","DOI":"10.1126\/scitranslmed.aav6221","article-title":"Increased soluble TREM2 in cerebrospinal fluid is associated with reduced cognitive and clinical decline in Alzheimer\u2019s disease","volume":"11","author":"Ewers","year":"2019","journal-title":"Sci. Transl. Med."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1177\/002215540004800713","article-title":"Cellular localization of gene expression for progranulin","volume":"48","author":"Daniel","year":"2000","journal-title":"J. Histochem. Cytochem."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.neuron.2017.06.026","article-title":"Loss of TMEM106B ameliorates lysosomal and frontotemporal dementia-related phenotypes in progranulin-deficient Mice","volume":"95","author":"Klein","year":"2017","journal-title":"Neuron"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"11929","DOI":"10.1523\/JNEUROSCI.1860-14.2014","article-title":"An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex","volume":"34","author":"Zhang","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Suh, H.S., Choi, N., Tarassishin, L., and Lee, S.C. (2012). Regulation of progranulin expression in human microglia and proteolysis of progranulin by matrix metalloproteinase-12 (MMP-12). PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0035115"},{"key":"ref_102","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_103","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_104","doi-asserted-by":"crossref","unstructured":"Palfree, R.G., Bennett, H.P., and Bateman, A. (2015). The evolution of the secreted regulatory protein progranulin. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0133749"},{"key":"ref_105","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_106","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_107","doi-asserted-by":"crossref","first-page":"6543","DOI":"10.2147\/JIR.S339254","article-title":"Progranulin as a potential therapeutic target in immune-mediated diseases","volume":"14","author":"Lan","year":"2021","journal-title":"J. Inflamm. Res."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1111\/imm.12241","article-title":"Progranulin promotes tumour necrosis factor-induced proliferation of suppressive mouse CD4(+) Foxp3(+) regulatory T cells","volume":"142","author":"Hu","year":"2014","journal-title":"Immunology"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1126\/science.1199214","article-title":"The growth factor progranulin binds to TNF receptors and is therapeutic against inflammatory arthritis in mice","volume":"332","author":"Tang","year":"2011","journal-title":"Science"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"e144016","DOI":"10.1172\/JCI144016","article-title":"TNFR2\/14-3-3epsilon signaling complex instructs macrophage plasticity in inflammation and autoimmunity","volume":"131","author":"Fu","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"2244","DOI":"10.1136\/annrheumdis-2014-205779","article-title":"Progranulin protects against osteoarthritis through interacting with TNF-alpha and beta-Catenin signalling","volume":"74","author":"Zhao","year":"2015","journal-title":"Ann. Rheum. Dis."},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"Du, H., Yang, C., Nana, A.L., Seeley, W.W., Smolka, M., and Hu, F. (2023). Progranulin inhibits phospholipase sPLA2-IIA to control neuroinflammation. bioRxiv.","DOI":"10.1101\/2023.04.06.535844"},{"key":"ref_113","first-page":"2438","article-title":"Proteinase 3 and neutrophil elastase enhance inflammation in mice by inactivating antinflammatory progranulin","volume":"118","author":"Kessenbrock","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1016\/S0092-8674(02)01141-8","article-title":"Conversion of proepithelin to epithelins: Roles of SLPI and elastase in host defense and wound repair","volume":"111","author":"Zhu","year":"2002","journal-title":"Cell"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1111\/j.1582-4934.2011.01350.x","article-title":"Progranulin contributes to endogenous mechanisms of pain defense after nerve injury in mice","volume":"16","author":"Lim","year":"2012","journal-title":"J. Cell Mol. Med."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"e5","DOI":"10.1016\/j.neurobiolaging.2011.06.017","article-title":"Extracellular progranulin protects cortical neurons from toxic insults by activating survival signaling","volume":"32","author":"Xu","year":"2011","journal-title":"Neurobiol. Aging"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"147312","DOI":"10.1016\/j.brainres.2021.147312","article-title":"Progranulin promotes functional recovery and neurogenesis in the subventricular zone of adult mice after cerebral ischemia","volume":"1757","author":"Liu","year":"2021","journal-title":"Brain Res."},{"key":"ref_118","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_119","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1016\/j.stemcr.2023.01.012","article-title":"Granulin loss of function in human mature brain organoids implicates astrocytes in TDP-43 pathology","volume":"18","author":"Koontz","year":"2023","journal-title":"Stem Cell Rep."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.nbd.2018.11.011","article-title":"Reduction of microglial progranulin does not exacerbate pathology or behavioral deficits in neuronal progranulin-insufficient mice","volume":"124","author":"Arrant","year":"2019","journal-title":"Neurobiol. Dis."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1093\/hmg\/ddz229","article-title":"Progranulin mutations result in impaired processing of prosaposin and reduced glucocerebrosidase activity","volume":"29","author":"Valdez","year":"2020","journal-title":"Hum. Mol. Genet."},{"key":"ref_122","doi-asserted-by":"crossref","unstructured":"Zhou, X., Paushter, D.H., Pagan, M.D., Kim, D., Nunez Santos, M., Lieberman, R.L., Overkleeft, H.S., Sun, Y., Smolka, M.B., and Hu, F. (2019). Progranulin deficiency leads to reduced glucocerebrosidase activity. PLoS ONE, 14.","DOI":"10.1101\/540450"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.ebiom.2016.10.010","article-title":"Progranulin recruits HSP70 to beta-glucocerebrosidase and is therapeutic against Gaucher disease","volume":"13","author":"Jian","year":"2016","journal-title":"EBioMedicine"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1083\/jcb.201502029","article-title":"Prosaposin facilitates sortilin-independent lysosomal trafficking of progranulin","volume":"210","author":"Zhou","year":"2015","journal-title":"J. Cell Biol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"15277","DOI":"10.1038\/ncomms15277","article-title":"Impaired prosaposin lysosomal trafficking in frontotemporal lobar degeneration due to progranulin mutations","volume":"8","author":"Zhou","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_126","doi-asserted-by":"crossref","unstructured":"Butler, V.J., Gao, F., Corrales, C.I., Cortopassi, W.A., Caballero, B., Vohra, M., Ashrafi, K., Cuervo, A.M., Jacobson, M.P., and Coppola, G. (2019). Age- and stress-associated C. elegans granulins impair lysosomal function and induce a compensatory HLH-30\/TFEB transcriptional response. PLoS Genet., 15.","DOI":"10.1371\/journal.pgen.1008295"},{"key":"ref_127","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_128","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1016\/j.braindev.2019.03.004","article-title":"Neuronal ceroid lipofuscinosis type-11 in an adolescent","volume":"41","author":"Kamate","year":"2019","journal-title":"Brain Dev."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1038\/s41582-019-0138-8","article-title":"Therapeutic landscape for Batten disease: Current treatments and future prospects","volume":"15","author":"Johnson","year":"2019","journal-title":"Nat. Rev. Neurol."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"2988","DOI":"10.1093\/hmg\/ddl241","article-title":"Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration","volume":"15","author":"Gass","year":"2006","journal-title":"Hum. Mol. Genet."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"eaah5642","DOI":"10.1126\/scitranslmed.aah5642","article-title":"Individuals with progranulin haploinsufficiency exhibit features of neuronal ceroid lipofuscinosis","volume":"9","author":"Ward","year":"2017","journal-title":"Sci. Transl. Med."},{"key":"ref_132","first-page":"76","article-title":"Behavioral variant frontotemporal dementia","volume":"25","author":"Seeley","year":"2019","journal-title":"Continuum"},{"key":"ref_133","first-page":"101","article-title":"Primary progressive aphasias and apraxia of speech","volume":"25","author":"Botha","year":"2019","journal-title":"Continuum"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"2194","DOI":"10.1038\/s41591-022-01942-9","article-title":"Temporal order of clinical and biomarker changes in familial frontotemporal dementia","volume":"28","author":"Staffaroni","year":"2022","journal-title":"Nat. Med."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1212\/01.wnl.0000319688.89790.7a","article-title":"Genetic variability in progranulin contributes to risk for clinically diagnosed Alzheimer disease","volume":"71","author":"Brouwers","year":"2008","journal-title":"Neurology"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"603","DOI":"10.3233\/JAD-2009-1170","article-title":"Rs5848 variant influences GRN mRNA levels in brain and peripheral mononuclear cells in patients with Alzheimer\u2019s disease","volume":"18","author":"Fenoglio","year":"2009","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1016\/S1474-4422(19)30320-5","article-title":"Identification of novel risk loci, causal insights, and heritable risk for Parkinson\u2019s disease: A meta-analysis of genome-wide association studies","volume":"18","author":"Nalls","year":"2019","journal-title":"Lancet Neurol."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1212\/01.wnl.0000289191.54852.75","article-title":"Progranulin genetic variability contributes to amyotrophic lateral sclerosis","volume":"71","author":"Sleegers","year":"2008","journal-title":"Neurology"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.1093\/brain\/awz099","article-title":"Limbic-predominant age-related TDP-43 encephalopathy (LATE): Consensus working group report","volume":"142","author":"Nelson","year":"2019","journal-title":"Brain"},{"key":"ref_140","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_141","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_142","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_143","doi-asserted-by":"crossref","unstructured":"Van Kampen, J.M., Baranowski, D., and Kay, D.G. (2014). Progranulin gene delivery protects dopaminergic neurons in a mouse model of Parkinson\u2019s disease. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0097032"},{"key":"ref_144","doi-asserted-by":"crossref","unstructured":"Laird, A.S., Van Hoecke, A., De Muynck, L., Timmers, M., Van den Bosch, L., Van Damme, P., and Robberecht, W. (2010). Progranulin is neurotrophic in vivo and protects against a mutant TDP-43 induced axonopathy. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0013368"},{"key":"ref_145","doi-asserted-by":"crossref","unstructured":"Zhao, Z., Anselmo, A.C., and Mitragotri, S. (2022). Viral vector-based gene therapies in the clinic. Bioeng. Transl. Med., 7.","DOI":"10.1002\/btm2.10258"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"1582","DOI":"10.1016\/j.gendis.2022.05.031","article-title":"Progranulin regulation of autophagy contributes to its chondroprotective effect in osteoarthritis","volume":"10","author":"Pan","year":"2023","journal-title":"Genes Dis."},{"key":"ref_147","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_148","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_149","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1186\/s13024-018-0281-5","article-title":"Early lysosomal maturation deficits in microglia triggers enhanced lysosomal activity in other brain cells of progranulin knockout mice","volume":"13","author":"Gotzl","year":"2018","journal-title":"Mol. Neurodegener."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1016\/j.neuron.2013.07.033","article-title":"Converging mechanisms in ALS and FTD: Disrupted RNA and protein homeostasis","volume":"79","author":"Ling","year":"2013","journal-title":"Neuron"},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1002\/ana.21154","article-title":"TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer\u2019s disease","volume":"61","author":"Lin","year":"2007","journal-title":"Ann. Neurol."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/j.brainres.2007.09.048","article-title":"Concurrence of TDP-43, tau and alpha-synuclein pathology in brains of Alzheimer\u2019s disease and dementia with Lewy bodies","volume":"1184","author":"Higashi","year":"2007","journal-title":"Brain Res."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/s00401-022-02444-1","article-title":"Frequency of LATE neuropathologic change across the spectrum of Alzheimer\u2019s disease neuropathology: Combined data from 13 community-based or population-based autopsy cohorts","volume":"144","author":"Nelson","year":"2022","journal-title":"Acta Neuropathol."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"6080","DOI":"10.1172\/JCI139741","article-title":"Truncated stathmin-2 is a marker of TDP-43 pathology in frontotemporal dementia","volume":"130","author":"Prudencio","year":"2020","journal-title":"J. Clin. Invest."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"2611","DOI":"10.1084\/jem.20160999","article-title":"Progranulin deficiency causes impairment of autophagy and TDP-43 accumulation","volume":"214","author":"Chang","year":"2017","journal-title":"J. Exp. Med."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1186\/s13024-016-0132-1","article-title":"Progranulin promotes peripheral nerve regeneration and reinnervation: Role of notch signaling","volume":"11","author":"Altmann","year":"2016","journal-title":"Mol. Neurodegener."},{"key":"ref_157","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_158","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.1002\/acn3.51165","article-title":"Adeno-associated virus serotype 1-based gene therapy for FTD caused by GRN mutations","volume":"7","author":"Hinderer","year":"2020","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"4651","DOI":"10.1016\/j.cell.2021.08.002","article-title":"Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic","volume":"184","author":"Logan","year":"2021","journal-title":"Cell"},{"key":"ref_160","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_161","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1007\/s00401-017-1668-z","article-title":"Alzheimer\u2019s Disease Neuroimaging, I. Opposing effects of progranulin deficiency on amyloid and tau pathologies via microglial TYROBP network","volume":"133","author":"Takahashi","year":"2017","journal-title":"Acta Neuropathol."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"260","DOI":"10.3389\/fncel.2020.00260","article-title":"Progranulin administration attenuates beta-amyloid deposition in the hippocampus of 5xFAD mice yhrough modulating BACE1 expression and microglial phagocytosis","volume":"14","author":"Guan","year":"2020","journal-title":"Front. Cell Neurosci."},{"key":"ref_163","doi-asserted-by":"crossref","unstructured":"Van Kampen, J.M., and Kay, D.G. (2017). Progranulin gene delivery reduces plaque burden and synaptic atrophy in a mouse model of Alzheimer\u2019s disease. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0182896"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1016\/j.bbamcr.2008.09.018","article-title":"Proteomics of the lysosome","volume":"1793","author":"Lubke","year":"2009","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"8094","DOI":"10.1002\/jcp.27588","article-title":"Autophagic dysfunction in Alzheimer\u2019s disease: Cellular and molecular mechanistic approaches to halt Alzheimer\u2019s pathogenesis","volume":"234","author":"Uddin","year":"2019","journal-title":"J. Cell Physiol."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1016\/j.neuron.2013.06.046","article-title":"Microglial beclin 1 regulates retromer trafficking and phagocytosis and is impaired in Alzheimer\u2019s disease","volume":"79","author":"Lucin","year":"2013","journal-title":"Neuron"},{"key":"ref_167","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_168","doi-asserted-by":"crossref","first-page":"e164919","DOI":"10.1172\/JCI164919","article-title":"Astroglial toxicity promotes synaptic degeneration in the thalamocortical circuit in frontotemporal dementia with GRN mutations","volume":"133","author":"Marsan","year":"2023","journal-title":"J. Clin. Investig."},{"key":"ref_169","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_170","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1038\/s41598-017-01587-6","article-title":"Accumulation of multiple neurodegenerative disease-related proteins in familial frontotemporal lobar degeneration associated with granulin mutation","volume":"7","author":"Hosokawa","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1186\/s40478-014-0078-x","article-title":"Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice","volume":"2","author":"Tanaka","year":"2014","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"311","DOI":"10.2353\/ajpath.2010.090915","article-title":"Accelerated lipofuscinosis and ubiquitination in granulin knockout mice suggest a role for progranulin in successful aging","volume":"177","author":"Ahmed","year":"2010","journal-title":"Am. J. Pathol."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"3955","DOI":"10.1172\/JCI63113","article-title":"Progranulin deficiency promotes neuroinflammation and neuron loss following toxin-induced injury","volume":"122","author":"Martens","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_174","doi-asserted-by":"crossref","unstructured":"Reich, M., Simon, M., Polke, B., Werner, G., Schrader, C., Paris, I., Robinson, S., Davis, S.S., de Melo, G.L., and Schlaphoff, L. (2023). Rescue of FTLD-associated TDP-43 pathology and neurodegeneration by peripheral AAV-mediated expression of brain-penetrant progranulin. bioRxiv.","DOI":"10.1101\/2023.07.14.549089"},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"5029","DOI":"10.1073\/pnas.1700477114","article-title":"Microglial NFkappaB-TNFalpha hyperactivation induces obsessive-compulsive behavior in mouse models of progranulin-deficient frontotemporal dementia","volume":"114","author":"Krabbe","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_176","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_177","doi-asserted-by":"crossref","first-page":"2850","DOI":"10.1093\/hmg\/ddx162","article-title":"Progranulin functions as a cathepsin D chaperone to stimulate axonal outgrowth in vivo","volume":"26","author":"Beel","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1002\/path.4043","article-title":"Cellular ageing, increased mortality and FTLD-TDP-associated neuropathology in progranulin knockout mice","volume":"228","author":"Wils","year":"2012","journal-title":"J. Pathol."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"107247","DOI":"10.1016\/j.isci.2023.107247","article-title":"AAV-GRN partially corrects motor deficits and ALS\/FTLD-related pathology in Tmem106b(\u2212\/\u2212)Grn(\u2212\/\u2212) mice","volume":"26","author":"Feng","year":"2023","journal-title":"iScience"},{"key":"ref_180","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_181","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/1750-1326-5-41","article-title":"Progranulin modulates zebrafish motoneuron development in vivo and rescues truncation defects associated with knockdown of survival motor neuron 1","volume":"5","author":"Chitramuthu","year":"2010","journal-title":"Mol. Neurodegener."},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"2541","DOI":"10.1016\/j.neurobiolaging.2013.04.022","article-title":"The neurotrophic properties of progranulin depend on the granulin E domain but do not require sortilin binding","volume":"34","author":"Herdewyn","year":"2013","journal-title":"Neurobiol. Aging"},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/j.nbd.2011.08.029","article-title":"Core features of frontotemporal dementia recapitulated in progranulin knockout mice","volume":"45","author":"Ghoshal","year":"2012","journal-title":"Neurobiol. Dis."},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1002\/glia.23091","article-title":"Progranulin protects against exaggerated axonal injury and astrogliosis following traumatic brain injury","volume":"65","author":"Menzel","year":"2017","journal-title":"Glia"},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"19579","DOI":"10.1523\/JNEUROSCI.4318-13.2013","article-title":"Progranulin deficiency promotes post-ischemic blood-brain barrier disruption","volume":"33","author":"Jackman","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"3931","DOI":"10.1002\/cne.22430","article-title":"Progranulin expression in the developing and adult murine brain","volume":"518","author":"Petkau","year":"2010","journal-title":"J. Comp. Neurol."},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1186\/s12974-017-1000-9","article-title":"Selective depletion of microglial progranulin in mice is not sufficient to cause neuronal ceroid lipofuscinosis or neuroinflammation","volume":"14","author":"Petkau","year":"2017","journal-title":"J. Neuroinflamm."},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"3430","DOI":"10.1002\/j.1460-2075.1994.tb06648.x","article-title":"Differential sorting of lysosomal enzymes in mannose 6-phosphate receptor-deficient fibroblasts","volume":"13","author":"Ludwig","year":"1994","journal-title":"EMBO J."},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"17068","DOI":"10.1523\/JNEUROSCI.4067-10.2010","article-title":"Neuronal LRP1 knockout in adult mice leads to impaired brain lipid metabolism and progressive, age-dependent synapse loss and neurodegeneration","volume":"30","author":"Liu","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"11992","DOI":"10.1038\/ncomms11992","article-title":"Prosaposin is a regulator of progranulin levels and oligomerization","volume":"7","author":"Nicholson","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1186\/s12967-023-04251-y","article-title":"Latozinemab, a novel progranulin-elevating therapy for frontotemporal dementia","volume":"21","author":"Kurnellas","year":"2023","journal-title":"J. Transl. Med."},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1007\/978-1-4939-3271-9_10","article-title":"Controlling AAV tropism in the nervous system with natural and engineered capsids","volume":"1382","author":"Castle","year":"2016","journal-title":"Methods Mol. Biol."},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1038\/s41573-019-0012-9","article-title":"Adeno-associated virus vector as a platform for gene therapy delivery","volume":"18","author":"Wang","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_194","doi-asserted-by":"crossref","unstructured":"de la Fuente, M., Lombardero, L., Gomez-Gonzalez, A., Solari, C., Angulo-Barturen, I., Acera, A., Vecino, E., Astigarraga, E., and Barreda-Gomez, G. (2021). Enzyme therapy: Current challenges and future perspectives. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22179181"},{"key":"ref_195","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1056\/NEJMoa011931","article-title":"Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin","volume":"346","author":"Casadevall","year":"2002","journal-title":"N. Engl. J. Med."},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1097\/01.ASN.0000107561.59698.42","article-title":"Anti-erythropoietin antibodies and pure red cell aplasia","volume":"15","author":"Rossert","year":"2004","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_197","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1093\/ndt\/gfg182","article-title":"Pure red-cell aplasia due to anti-erythropoietin antibodies","volume":"18","author":"Eckardt","year":"2003","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_198","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1038\/nature04818","article-title":"Computational redesign of endonuclease DNA binding and cleavage specificity","volume":"441","author":"Ashworth","year":"2006","journal-title":"Nature"},{"key":"ref_199","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1159\/000500804","article-title":"Recovery of vision following enzyme replacement therapy in a patient with mucopolysaccharidosis type II, Hunter syndrome","volume":"10","author":"Yamanishi","year":"2019","journal-title":"Case Rep. Ophthalmol."},{"key":"ref_200","doi-asserted-by":"crossref","unstructured":"Ventura, E., Ducci, G., Benot Dominguez, R., Ruggiero, V., Belfiore, A., Sacco, E., Vanoni, M., Iozzo, R.V., Giordano, A., and Morrione, A. (2023). Progranulin oncogenic network in solid tumors. Cancers, 15.","DOI":"10.3390\/cancers15061706"},{"key":"ref_201","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1086\/318809","article-title":"A phase 1\/2 clinical trial of enzyme replacement in fabry disease: Pharmacokinetic, substrate clearance, and safety studies","volume":"68","author":"Eng","year":"2001","journal-title":"Am. J. Hum. Genet."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/21\/15946\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:16:32Z","timestamp":1760130992000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/21\/15946"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,3]]},"references-count":201,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2023,11]]}},"alternative-id":["ijms242115946"],"URL":"https:\/\/doi.org\/10.3390\/ijms242115946","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,3]]}}}