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.

Keywords: ALS; FTLD; TDP-43; degradation system; prion; profilin 1.

FIGURE 1.

Conversion of normal TDP-43 into prion-like species by ALS-linked PFN1 mutants. PFN1 with mutations that cause ALS forms aggregates in the cytoplasm. TDP-43 localized in the cytoplasm for its production or transportation from nucleus is sequestered into PFN1 aggregates, where it is converted into prion-like species, and forms TDP-43 aggregates. Furthermore, these TDP-43 aggregates serve as a template for conversion of normal TDP-43 into prion-like TDP-43 aggregates. As a result, TDP-43 filaments are formed. Thus, TDP-43 aggregation is facilitated firstly by sequestration of TDP-43 into PFN1 aggregates and secondly by self-template-type aggregation of prion-like TDP-43.