biostudies-literatureOtte CGRobert Packard Center for ALS at Johns HopkinsNIA NIH HHSALS AssociationUniversity of Pittsburgh Center for Protein Conformational DiseasesNINDS NIH HHSNational Institutes of HealthLiveLikeLou Center for ALS Research at the University of Pittsburgh Brain InstituteMuscular Dystrophy Association105078https://www.ebi.ac.uk/biostudies/studies/S-EPMC9040199biostudies-literatureUnknown146TDP-43 is a predominantly nuclear DNA/RNA binding protein that is often mislocalized into insoluble cytoplasmic inclusions in post-mortem patient tissue in a variety of neurodegenerative disorders including Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal dementia (FTD). The underlying causes of TDP-43 proteinopathies remain unclear, but recent studies indicate the formation of these protein assemblies is driven by aberrant phase transitions of RNA deficient TDP-43. Technical limitations have prevented our ability to understand how TDP-43 proteinopathy relates to disease pathogenesis. Current animal models of TDP-43 proteinopathy often rely on overexpression of wild-type TDP-43 to non-physiological levels that may initiate neurotoxicity through nuclear gain of function mechanisms, orNeurobiology of diseaseOptogenetic TDP-43 nucleation induces persistent insoluble species and progressive motor dysfunction in vivo.PMC9040199R01NS081303R01NS105756R21 AG064940R21 NS100055R01 NS105756R21NS111768R01 NS081303R21NS101661R21 NS111768R21 NS101661R21AG064940R21NS100055Otte CGMann JRDonnelly CJPyles NJGleixner AMRamesh NFortuna TRPandey UBfalseOptogenetic TDP-43 nucleation induces persistent insoluble species and progressive motor dysfunction in vivo.TDP-43 is a predominantly nuclear DNA/RNA binding protein that is often mislocalized into insoluble cytoplasmic inclusions in post-mortem patient tissue in a variety of neurodegenerative disorders including Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal dementia (FTD). The underlying causes of TDP-43 proteinopathies remain unclear, but recent studies indicate the formation of these protein assemblies is driven by aberrant phase transitions of RNA deficient TDP-43. Technical limitations have prevented our ability to understand how TDP-43 proteinopathy relates to disease pathogenesis. Current animal models of TDP-43 proteinopathy often rely on overexpression of wild-type TDP-43 to non-physiological levels that may initiate neurotoxicity through nuclear gain of function mechanisms, or2020-01-01T00:00:00Z2020 Dec2025-04-04T07:44:03.055Z2025-04-04T07:44:03.055ZS-EPMC90401993292706210.1016/j.nbd.2020.105078