Endocytosis regulates TDP-43 toxicity and turnover

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作者
Guangbo Liu
Alyssa N. Coyne
Fen Pei
Spencer Vaughan
Matthew Chaung
Daniela C. Zarnescu
J. Ross Buchan
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[1] University of Arizona,Department of Molecular and Cellular Biology
[2] University of Arizona,Departments of Neuroscience and Neurology
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Nature Communications | / 8卷
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摘要
Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron degenerative disease. ALS-affected motor neurons exhibit aberrant localization of a nuclear RNA binding protein, TDP-43, into cytoplasmic aggregates, which contributes to pathology via unclear mechanisms. Here, we demonstrate that TDP-43 turnover and toxicity depend in part upon the endocytosis pathway. TDP-43 inhibits endocytosis, and co-localizes strongly with endocytic proteins, including in ALS patient tissue. Impairing endocytosis increases TDP-43 toxicity, aggregation, and protein levels, whereas enhancing endocytosis reverses these phenotypes. Locomotor dysfunction in a TDP-43 ALS fly model is also exacerbated and suppressed by impairment and enhancement of endocytic function, respectively. Thus, endocytosis dysfunction may be an underlying cause of ALS pathology.
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