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
• degradation system
• FTLD
• profilin 1
• prion
• TDP-43

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ACKNOWLEDGMENTS

We thank Genjiro Suzuki for his comments on the manuscript.

Funding

Funding was provided by JSPS KAKENHI Grant Number 15K18370, 14J03307 (to YT), 23228004 (to MH), MEXT KAKENHI Grant Numbers 26117005, 23240050 (to MH), and MHLW Grant ID Number 12946221 (to MH).