title: Profilin 1 mutants form aggregates that induce accumulation of prion-like TDP-43.
abstract: Mutations in the profilin 1 (PFN1) gene have been identified as a cause of familial amyotrophic lateral sclerosis (ALS), and neuropathological studies indicate that TDP-43 is accumulated in brains of patients with PFN1 mutation. Here, we investigated the role of PFN1 mutations in the formation of prion-like abnormal TDP-43. Expression of PFN1 with pathogenic mutations resulted in the formation of cytoplasmic aggregates positive for p62 and ubiquitin, and these aggregates sequestered endogenous TDP-43. TDP-43 accumulation was facilitated in the presence of proteasome or lysosome inhibitor. Co-expression of mutant PFN1 and TDP-43 increased the levels of detergent-insoluble and phosphorylated TDP-43, and this increase required the C-terminal region of TDP-43. Moreover, detergent-insoluble fractions prepared from cells expressing ALS-linked mutant PFN1 induced seed-dependent accumulation of TDP-43. These findings indicate that expression of PFN1 mutants induces accumulation of TDP-43, and promotes conversion of normal TDP-43 into an abnormal form. These results provide new insight into the mechanisms of TDP-43 proteinopathies and other diseases associated with amyloid-like protein deposition.
authors.affiliation: a Dementia Research Project, Tokyo Metropolitan Institute of Medical Science , Tokyo , Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: a Dementia Research Project, Tokyo Metropolitan Institute of Medical Science , Tokyo , Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Hasegawa
mesh_terms: D001921:Brain / Q000378:metabolism / Q000473:pathology*; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D009154:Mutation; D011328:Prions / Q000378:metabolism*; D051304:Profilins / Q000235:genetics* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D066263:Protein Aggregation, Pathological; D057177:TDP-43 Proteinopathies / Q000235:genetics; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C495738:PFN1 protein, human; D011328:Prions; D051304:Profilins; C000598624:TARDBP protein, human; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex
keywords: ALS; FTLD; TDP-43; degradation system; prion; profilin 1