Endocytosis regulates TDP-43 toxicity and turnover.

Nat Commun 2017 12 12;8(1):2092. Epub 2017 Dec 12.

Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ, 85721, USA.

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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Source
http://dx.doi.org/10.1038/s41467-017-02017-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727062PMC
December 2017

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