期刊
EXPERIMENTAL NEUROLOGY
卷 345, 期 -, 页码 -出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.expneurol.2021.113833
关键词
TDP-43; UBE2N; Aggregate; Ubiquitin-proteasomal system; Non-human primate
资金
- National Key Research and Development Program [2017YFA0105102]
- Guangzhou Key Research Program on Brain Science [202007030008]
- Key Field Research and Development Program of Guangdong province [2018B030337001, 2017B020231001]
- Guangdong Key Laboratory of non-human primate research [2020B121201006]
- National Science Foundation of China [81830032, 31872779, 31500826, 82071421, 81873736]
- Science and Technology Projects in Guangzhou [202102080630030024]
The cytoplasmic inclusions of nuclear TAR DNA-binding protein 43 (TDP-43) are a pathological hallmark in several neurological disorders, and expressing mutant TDP-43 in monkeys can mimic the cytoplasmic mislocalization seen in patient brains. This study suggests that cytoplasmic mutant TDP-43 may inhibit proteasomal activity, leading to the age-dependent accumulation of misfolded proteins in the brain.
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.
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