{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T03:05:53Z","timestamp":1783998353065,"version":"3.55.0"},"reference-count":71,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T00:00:00Z","timestamp":1783468800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Innovative Drug Research and Development National Science and Technology Major Project","award":["2025ZD1802600"],"award-info":[{"award-number":["2025ZD1802600"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>TAR DNA binding protein (TARDBP) is one of the major causative genes of amyotrophic lateral sclerosis (ALS), which drives disease progression through both gain-of-toxicity (GOT) and loss-of-function (LOF) mechanisms. The mutant TDP-43 exhibits aberrant nucleocytoplasmic distribution and forms cytotoxic hyperphosphorylated aggregates, a process that can be robustly recapitulated in vitro. Thus, functional assays in cell lines serve as a reliable metric for the pathogenicity classification of TARDBP variants. In this study, we performed in vitro experiments to classify the pathogenicity of 28 TARDBP variants of uncertain significance (VUS) among the 172 previously reported TARDBP variants. 22 of these VUS were determined to be functionally abnormal, of which 12 could be further classified as likely pathogenic (LP) variants according to American College of Medical Genetics (ACMG) and the ClinGen Sequence Variant Interpretation (SVI) Working Group guidelines. We also summarized the clinical characteristics of 35 ALS patients carrying 12 variants in the TARDBP gene. Pathogenic missense variants were predominantly clustered in the C-terminal domain (CTD) of TARDBP. Variants in TARDBP exon 6 may lead to an earlier age at onset. ALS caused by TARDBP mutations exhibits marked phenotypic heterogeneity, along with incomplete penetrance in carriers. Patient-derived primary skin fibroblasts serve as a feasible cellular model for the functional assessment of variant pathogenicity. Our findings expand the TARDBP mutation spectrum, and provides a preliminary basis for preclinical research on TARDBP-targeted therapies for ALS.<\/jats:p>","DOI":"10.3390\/cells15141232","type":"journal-article","created":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T14:27:23Z","timestamp":1783520843000},"page":"1232","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pathogenicity Classification of TARDBP Variants of Uncertain Significance: An Integrative Clinical Characterization and Functional Validation"],"prefix":"10.3390","volume":"15","author":[{"given":"Chao-Sen","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Medical Genetics and Center for Rare Diseases, Second Affiliated Hospital, Zhejiang University School of Medicine, and Zhejiang Key Laboratory of Rare Diseases for Precision Medicine and Clinical Translation, Hangzhou 310002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics and Center for Rare Diseases, Second Affiliated Hospital, Zhejiang University School of Medicine, and Zhejiang Key Laboratory of Rare Diseases for Precision Medicine and Clinical Translation, Hangzhou 310002, China"},{"name":"Nanhu Brain-Computer Interface Institute, Hangzhou 310002, China"},{"name":"Department of Neurology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9588-2717","authenticated-orcid":false,"given":"Jia-Li","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics and Center for Rare Diseases, Second Affiliated Hospital, Zhejiang University School of Medicine, and Zhejiang Key Laboratory of Rare Diseases for Precision Medicine and Clinical Translation, Hangzhou 310002, China"},{"name":"Nanhu Brain-Computer Interface Institute, Hangzhou 310002, China"},{"name":"Department of Neurology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin-Yan","family":"Lou","sequence":"additional","affiliation":[{"name":"College of Laboratory Medicine (College of Life Sciences), Wenzhou Medical University, Wenzhou 325035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong-Ting","family":"Lv","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics and Center for Rare Diseases, Second Affiliated Hospital, Zhejiang University School of Medicine, and Zhejiang Key Laboratory of Rare Diseases for Precision Medicine and Clinical Translation, Hangzhou 310002, China"},{"name":"Department of Neurology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tan-Xia","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics and Center for Rare Diseases, Second Affiliated Hospital, Zhejiang University School of Medicine, and Zhejiang Key Laboratory of Rare Diseases for Precision Medicine and Clinical Translation, Hangzhou 310002, China"},{"name":"Nanhu Brain-Computer Interface Institute, Hangzhou 310002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5434-9625","authenticated-orcid":false,"given":"Hai-Feng","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics and Center for Rare Diseases, Second Affiliated Hospital, Zhejiang University School of Medicine, and Zhejiang Key Laboratory of Rare Diseases for Precision Medicine and Clinical Translation, Hangzhou 310002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng-Mei","family":"Zou","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics and Center for Rare Diseases, Second Affiliated Hospital, Zhejiang University School of Medicine, and Zhejiang Key Laboratory of Rare Diseases for Precision Medicine and Clinical Translation, Hangzhou 310002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi-Ying","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics and Center for Rare Diseases, Second Affiliated Hospital, Zhejiang University School of Medicine, and Zhejiang Key Laboratory of Rare Diseases for Precision Medicine and Clinical Translation, Hangzhou 310002, China"},{"name":"Nanhu Brain-Computer Interface Institute, Hangzhou 310002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2203-0046","authenticated-orcid":false,"given":"Hong-Fu","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics and Center for Rare Diseases, Second Affiliated Hospital, Zhejiang University School of Medicine, and Zhejiang Key Laboratory of Rare Diseases for Precision Medicine and Clinical Translation, Hangzhou 310002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1159\/000351153","article-title":"Global epidemiology of amyotrophic lateral sclerosis: A systematic review of the published literature","volume":"41","author":"Chio","year":"2013","journal-title":"Neuroepidemiology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1038\/35097565","article-title":"From Charcot to Lou Gehrig: Deciphering selective motor neuron death in ALS","volume":"2","author":"Cleveland","year":"2001","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.neuron.2006.09.018","article-title":"ALS: A disease of motor neurons and their nonneuronal neighbors","volume":"52","author":"Boillee","year":"2006","journal-title":"Neuron"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1097\/WCO.0000000000001294","article-title":"The genetics of amyotrophic lateral sclerosis","volume":"37","author":"Nijs","year":"2024","journal-title":"Curr. Opin. Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1002\/ana.21392","article-title":"TDP-43 mutation in familial amyotrophic lateral sclerosis","volume":"63","author":"Yokoseki","year":"2008","journal-title":"Ann. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1126\/science.1166066","article-title":"Mutations in the FUS\/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis","volume":"323","author":"Kwiatkowski","year":"2009","journal-title":"Science"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1038\/362059a0","article-title":"Mutations in Cu\/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis","volume":"362","author":"Rosen","year":"1993","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.neuron.2011.09.011","article-title":"Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS","volume":"72","author":"Mackenzie","year":"2011","journal-title":"Neuron"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3584","DOI":"10.1128\/jvi.69.6.3584-3596.1995","article-title":"Cloning and characterization of a novel cellular protein, TDP-43, that binds to human immunodeficiency virus type 1 TAR DNA sequence motifs","volume":"69","author":"Ou","year":"1995","journal-title":"J. Virol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"36337","DOI":"10.1074\/jbc.M104236200","article-title":"Characterization and functional implications of the RNA binding properties of nuclear factor TDP-43, a novel splicing regulator of CFTR exon 9","volume":"276","author":"Buratti","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Prasad, A., Bharathi, V., Sivalingam, V., Girdhar, A., and Patel, B.K. (2019). Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis. Front. Mol. Neurosci., 12.","DOI":"10.3389\/fnmol.2019.00025"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3778","DOI":"10.1242\/jcs.038950","article-title":"Structural determinants of the cellular localization and shuttling of TDP-43","volume":"121","author":"Ayala","year":"2008","journal-title":"J. Cell Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1242\/jcs.051672","article-title":"Prion-like disorders: Blurring the divide between transmissibility and infectivity","volume":"123","author":"Cushman","year":"2010","journal-title":"J. Cell Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1668","DOI":"10.1126\/science.1154584","article-title":"TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis","volume":"319","author":"Sreedharan","year":"2008","journal-title":"Science"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"R156","DOI":"10.1093\/hmg\/ddp303","article-title":"Mutations in TDP-43 link glycine-rich domain functions to amyotrophic lateral sclerosis","volume":"18","author":"Pesiridis","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/S1474-4422(08)70071-1","article-title":"TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: A genetic and histopathological analysis","volume":"7","author":"Leverenz","year":"2008","journal-title":"Lancet Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"20329","DOI":"10.1074\/jbc.M109.010264","article-title":"TDP-43 is intrinsically aggregation-prone, and amyotrophic lateral sclerosis-linked mutations accelerate aggregation and increase toxicity","volume":"284","author":"Johnson","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1661","DOI":"10.1007\/s00702-008-0137-1","article-title":"Fine structural analysis of the neuronal inclusions of frontotemporal lobar degeneration with TDP-43 proteinopathy","volume":"115","author":"Thorpe","year":"2008","journal-title":"J. Neural Transm."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1002\/ana.21425","article-title":"Phosphorylated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis","volume":"64","author":"Hasegawa","year":"2008","journal-title":"Ann. Neurol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1186\/s40478-024-01914-9","article-title":"Decoding TDP-43: The molecular chameleon of neurodegenerative diseases","volume":"12","author":"Zeng","year":"2024","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_21","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_22","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1007\/s00401-008-0477-9","article-title":"Phosphorylation of S409\/410 of TDP-43 is a consistent feature in all sporadic and familial forms of TDP-43 proteinopathies","volume":"117","author":"Neumann","year":"2009","journal-title":"Acta Neuropathol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1038\/nm.4130","article-title":"The inhibition of TDP-43 mitochondrial localization blocks its neuronal toxicity","volume":"22","author":"Wang","year":"2016","journal-title":"Nat. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1038\/s41594-020-00537-7","article-title":"TDP-43 aggregation induced by oxidative stress causes global mitochondrial imbalance in ALS","volume":"28","author":"Zuo","year":"2021","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_25","first-page":"86","article-title":"TDP-43 proteinopathies: A new wave of neurodegenerative diseases","volume":"92","author":"Orie","year":"2020","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Wood, A., Gurfinkel, Y., Polain, N., Lamont, W., and Lyn Rea, S. (2021). Molecular Mechanisms Underlying TDP-43 Pathology in Cellular and Animal Models of ALS and FTLD. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22094705"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s13024-020-00397-1","article-title":"The role of TDP-43 mislocalization in amyotrophic lateral sclerosis","volume":"15","author":"Suk","year":"2020","journal-title":"Mol. Neurodegener."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1007\/s00401-019-02077-x","article-title":"The basis of clinicopathological heterogeneity in TDP-43 proteinopathy","volume":"138","author":"Kawakami","year":"2019","journal-title":"Acta Neuropathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1038\/s41593-017-0047-3","article-title":"TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS\/FTD","volume":"21","author":"Chou","year":"2018","journal-title":"Nat. Neurosci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1038\/nn.2779","article-title":"Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43","volume":"14","author":"Polymenidou","year":"2011","journal-title":"Nat. Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1016\/j.bbrc.2006.10.093","article-title":"TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis","volume":"351","author":"Arai","year":"2006","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1093\/brain\/awt029","article-title":"Loss of TDP-43 causes age-dependent progressive motor neuron degeneration","volume":"136","author":"Iguchi","year":"2013","journal-title":"Brain"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.neuroscience.2015.02.046","article-title":"Proteomic analyses reveal that loss of TDP-43 affects RNA processing and intracellular transport","volume":"293","author":"Stalekar","year":"2015","journal-title":"Neuroscience"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1523\/JNEUROSCI.4988-09.2010","article-title":"Cytoplasmic mislocalization of TDP-43 is toxic to neurons and enhanced by a mutation associated with familial amyotrophic lateral sclerosis","volume":"30","author":"Barmada","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1038\/nrn3121","article-title":"Gains or losses: Molecular mechanisms of TDP43-mediated neurodegeneration","volume":"13","author":"Lee","year":"2011","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"EMBJ201798684","DOI":"10.15252\/embj.201798684","article-title":"Mice with endogenous TDP-43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis","volume":"37","author":"Fratta","year":"2018","journal-title":"EMBO J."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Lanznaster, D., Bourgeais, J., Bruno, C., Hergesheimer, R.C., Thepault, R.A., Vourc\u2019h, P., Corcia, P., Andres, C.R., Herault, O., and Blasco, H. (2019). TDP-43-Mediated Toxicity in HEK293T Cells: A Fast and Reproducible Protocol To Be Employed in the Search of New Therapeutic Options against Amyotrophic Lateral Sclerosis. Cells, 9.","DOI":"10.3390\/cells9010068"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s13073-019-0690-2","article-title":"Recommendations for application of the functional evidence PS3\/BS3 criterion using the ACMG\/AMP sequence variant interpretation framework","volume":"12","author":"Brnich","year":"2019","journal-title":"Genome Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2229.e11","DOI":"10.1016\/j.neurobiolaging.2012.03.014","article-title":"Screening of the TARDBP gene in familial and sporadic amyotrophic lateral sclerosis patients of Chinese origin","volume":"33","author":"Zou","year":"2012","journal-title":"Neurobiol. Aging"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1038\/jhg.2012.24","article-title":"Novel TARDBP mutations in Nordic ALS patients","volume":"57","author":"Chiang","year":"2012","journal-title":"J. Hum. Genet."},{"key":"ref_41","first-page":"4473","article-title":"Reduced stress granule formation and cell death in fibroblasts with the A382T mutation of TARDBP gene: Evidence for loss of TDP-43 nuclear function","volume":"25","author":"Orru","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1093\/hmg\/ddp534","article-title":"Gain and loss of function of ALS-related mutations of TARDBP (TDP-43) cause motor deficits in vivo","volume":"19","author":"Kabashi","year":"2010","journal-title":"Hum. Mol. Genet."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Rubio, M.A., Herrando-Grabulosa, M., Velasco, R., Blasco, I., Povedano, M., and Navarro, X. (2022). TDP-43 Cytoplasmic Translocation in the Skin Fibroblasts of ALS Patients. Cells, 11.","DOI":"10.3390\/cells11020209"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Masi, M., Attanzio, A., Racchi, M., Wolozin, B., Borella, S., Biundo, F., and Buoso, E. (2022). Proteostasis Deregulation in Neurodegeneration and Its Link with Stress Granules: Focus on the Scaffold and Ribosomal Protein RACK1. Cells, 11.","DOI":"10.3390\/cells11162590"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"179033","DOI":"10.1016\/j.ejphar.2026.179033","article-title":"Ribosome impairment, tau alternative splicing, and stress granules: A convergent axis of neuronal vulnerability driving Alzheimer\u2019s disease","volume":"1030","author":"Masi","year":"2026","journal-title":"Eur. J. Pharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e13215","DOI":"10.1111\/bpa.13215","article-title":"Colocalization of TDP-43 and stress granules at the early stage of TDP-43 aggregation in amyotrophic lateral sclerosis","volume":"34","author":"Mori","year":"2024","journal-title":"Brain Pathol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3461","DOI":"10.1093\/brain\/awab217","article-title":"TDP-43 stabilizes G3BP1 mRNA: Relevance to amyotrophic lateral sclerosis\/frontotemporal dementia","volume":"144","author":"Sidibe","year":"2021","journal-title":"Brain"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1038\/ng.132","article-title":"TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis","volume":"40","author":"Kabashi","year":"2008","journal-title":"Nat. Genet."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Francois-Moutal, L., Perez-Miller, S., Scott, D.D., Miranda, V.G., Mollasalehi, N., and Khanna, M. (2019). Structural Insights Into TDP-43 and Effects of Post-translational Modifications. Front. Mol. Neurosci., 12.","DOI":"10.3389\/fnmol.2019.00301"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"7512","DOI":"10.1074\/jbc.M111.288720","article-title":"Cellular model of TAR DNA-binding protein 43 (TDP-43) aggregation based on its C-terminal Gln\/Asn-rich region","volume":"287","author":"Budini","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"6196","DOI":"10.1038\/s41598-017-06263-3","article-title":"The N-terminal dimerization is required for TDP-43 splicing activity","volume":"7","author":"Jiang","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/s41586-022-04436-3","article-title":"TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A","volume":"603","author":"Brown","year":"2022","journal-title":"Nature"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1126\/science.abq5622","article-title":"Mechanism of STMN2 cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies","volume":"379","author":"Baughn","year":"2023","journal-title":"Science"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1126\/science.aab0983","article-title":"TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD","volume":"349","author":"Ling","year":"2015","journal-title":"Science"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.molmed.2013.11.003","article-title":"TDP-43-mediated neurodegeneration: Towards a loss-of-function hypothesis?","volume":"20","author":"Callaerts","year":"2014","journal-title":"Trends Mol. Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1038\/s41593-018-0293-z","article-title":"Premature polyadenylation-mediated loss of stathmin-2 is a hallmark of TDP-43-dependent neurodegeneration","volume":"22","author":"Melamed","year":"2019","journal-title":"Nat. Neurosci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1038\/s41593-018-0300-4","article-title":"ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair","volume":"22","author":"Klim","year":"2019","journal-title":"Nat. Neurosci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1186\/s13024-025-00839-8","article-title":"Molecular mechanisms and consequences of TDP-43 phosphorylation in neurodegeneration","volume":"20","author":"Kellett","year":"2025","journal-title":"Mol. Neurodegener."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1007\/s11357-021-00383-5","article-title":"Regulation of TDP-43 phosphorylation in aging and disease","volume":"43","author":"Eck","year":"2021","journal-title":"Geroscience"},{"key":"ref_60","first-page":"e108443","article-title":"Disease-linked TDP-43 hyperphosphorylation suppresses TDP-43 condensation and aggregation","volume":"41","author":"Simonetti","year":"2022","journal-title":"EMBO J."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Li, H.Y., Yeh, P.A., Chiu, H.C., Tang, C.Y., and Tu, B.P. (2011). Hyperphosphorylation as a defense mechanism to reduce TDP-43 aggregation. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0023075"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"5089","DOI":"10.1074\/jbc.M116.753913","article-title":"Heat Shock-induced Phosphorylation of TAR DNA-binding Protein 43 (TDP-43) by MAPK\/ERK Kinase Regulates TDP-43 Function","volume":"292","author":"Li","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"e202302048","DOI":"10.1083\/jcb.202302048","article-title":"IkappaB kinase phosphorylates cytoplasmic TDP-43 and promotes its proteasome degradation","volume":"223","author":"Iguchi","year":"2024","journal-title":"J. Cell Biol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"3353","DOI":"10.1093\/hmg\/ddp275","article-title":"Truncation and pathogenic mutations facilitate the formation of intracellular aggregates of TDP-43","volume":"18","author":"Nonaka","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.1111\/ene.15727","article-title":"Evaluating the contribution of the gene TARDBP in Italian patients with amyotrophic lateral sclerosis","volume":"30","author":"Lattante","year":"2023","journal-title":"Eur. J. Neurol."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Xiong, H.L., Wang, J.Y., Sun, Y.M., Wu, J.J., Chen, Y., Qiao, K., Zheng, Q.J., Zhao, G.X., and Wu, Z.Y. (2010). Association between novel TARDBP mutations and Chinese patients with amyotrophic lateral sclerosis. BMC Med. Genet., 11.","DOI":"10.1186\/1471-2350-11-8"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Zhang, Z., Almeida, S., Lu, Y., Nishimura, A.L., Peng, L., Sun, D., Wu, B., Karydas, A.M., Tartaglia, M.C., and Fong, J.C. (2013). Downregulation of microRNA-9 in iPSC-derived neurons of FTD\/ALS patients with TDP-43 mutations. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0076055"},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Zanini, G., Selleri, V., Nasi, M., De Gaetano, A., Martinelli, I., Gianferrari, G., Lofaro, F.D., Boraldi, F., Mandrioli, J., and Pinti, M. (2022). Mitochondrial and Endoplasmic Reticulum Alterations in a Case of Amyotrophic Lateral Sclerosis Caused by TDP-43 A382T Mutation. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231911881"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/1750-1172-6-4","article-title":"Sensory and motor neuronopathy in a patient with the A382P TDP-43 mutation","volume":"6","author":"Camdessanche","year":"2011","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Waldron, F.M., Langerova, T., Rahmanova, A., Read, F.L., Spence, H., Roberts, K., Macleod, A.D., Pattle, S.B., Hanna, K., and Gregory, J.M. (2025). Skin TDP-43 pathology as a candidate biomarker for predicting amyotrophic lateral sclerosis decades prior to motor symptom onset. bioRxiv.","DOI":"10.1101\/2025.04.10.648122"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Nguyen, L. (2024). Updates on Disease Mechanisms and Therapeutics for Amyotrophic Lateral Sclerosis. Cells, 13.","DOI":"10.3390\/cells13110888"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/14\/1232\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T02:48:07Z","timestamp":1783997287000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/14\/1232"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,8]]},"references-count":71,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["cells15141232"],"URL":"https:\/\/doi.org\/10.3390\/cells15141232","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,8]]}}}