Endocytosis regulates TDP-43 toxicity and turnover

Guangbo Liu, Alyssa N. Coyne, Fen Pei, Spencer Vaughan, Matthew Chaung, Daniela C. Zarnescu and J. Ross Buchan ()
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Guangbo Liu: University of Arizona
Alyssa N. Coyne: University of Arizona
Fen Pei: University of Arizona
Spencer Vaughan: University of Arizona
Matthew Chaung: University of Arizona
Daniela C. Zarnescu: University of Arizona
J. Ross Buchan: University of Arizona

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/s41467-017-02017-x

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