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Nat Commun. 2017 Dec 12;8(1):2092. doi: 10.1038/s41467-017-02017-x.

Endocytosis regulates TDP-43 toxicity and turnover.

Author information

1
Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ, 85721, USA.
2
Departments of Neuroscience and Neurology, University of Arizona, Tucson, AZ, 85721, USA.
3
Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ, 85721, USA. rbuchan@email.arizona.edu.

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.

PMID:
29233983
PMCID:
PMC5727062
DOI:
10.1038/s41467-017-02017-x
[Indexed for MEDLINE]
Free PMC Article

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