Cytoplasmic TDP-43 impairs the activity of the ubiquitin-proteasome system.

The cytoplasmic inclusions of nuclear TAR DNA-binding protein 43 (TDP-43) are a pathologic hallmark in amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTD), and other neurological disorders. We reported that expressing mutant TDP-43(M337V) in rhesus monkeys can mimic the cytoplasmic mislocalization of mutant TDP-43 seen in patient brains. Here we investigated how cytoplasmic mutant TDP-43 mediates neuropathology. We found that C-terminal TDP-43 fragments are primarily localized in the cytoplasm and that the age-dependent elevated UBE2N promotes the accumulation of cytoplasmic C-terminal TDP-43 via K63 ubiquitination. Immunoprecipitation and mass spectrometry revealed that cytoplasmic mutant TDP-43 interacts with proteasome assembly proteins PSMG2 and PSD13, which might lead to the impairment of the proteasomal activity. Our findings suggest that cytoplasmic TDP-43 may participate in age-dependent accumulation of misfolded proteins in the brain by inhibiting the UPS activity.