期刊
FRONTIERS IN CELLULAR NEUROSCIENCE
卷 15, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fncel.2021.625665
关键词
neurodegenerative disorders; TDP-43 proteinopathies; ALS; FTD; nucleolin; misfolded proteins; nucleo-cytoplasmic transport
资金
- University of Padova [BIRD202151/20]
TDP-43 is a nuclear protein implicated in neurodegenerative disorders, with its misfolding and aggregation playing a key role in their etiopathology. Nucleolar protein nucleolin (NCL) has been identified as a potent suppressor of TDP-43 toxicity, alleviating its damage in both yeast and human cells. The findings suggest that NCL could promote TDP-43 nuclear retention, reducing the formation of toxic cytosolic TDP-43 inclusions.
TDP-43 is a nuclear protein involved in pivotal processes, extensively studied for its implication in neurodegenerative disorders. TDP-43 cytosolic inclusions are a common neuropathologic hallmark in amyotrophic lateral sclerosis (ALS) and related diseases, and it is now established that TDP-43 misfolding and aggregation play a key role in their etiopathology. TDP-43 neurotoxic mechanisms are not yet clarified, but the identification of proteins able to modulate TDP-43-mediated damage may be promising therapeutic targets for TDP-43 proteinopathies. Here we show by the use of refined yeast models that the nucleolar protein nucleolin (NCL) acts as a potent suppressor of TDP-43 toxicity, restoring cell viability. We provide evidence that NCL co-expression is able to alleviate TDP-43-induced damage also in human cells, further supporting its beneficial effects in a more consistent pathophysiological context. Presented data suggest that NCL could promote TDP-43 nuclear retention, reducing the formation of toxic cytosolic TDP-43 inclusions.
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