Coyne, Alyssa N.
Zarnescu, Daniela C.
Buchan, J. Ross
AffiliationUniv Arizona, Dept Mol & Cellular Biol
MetadataShow full item record
PublisherNATURE PUBLISHING GROUP
CitationEndocytosis regulates TDP-43 toxicity and turnover 2017, 8 (1) Nature Communications
Rights© The Author(s) 2017. This article is licensed under a Creative Commons Attribution 4.0 International License.
Collection InformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at firstname.lastname@example.org.
AbstractAmyotrophic 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.
VersionFinal published version
SponsorsNIH [RO1-GM1145664, RO1 NS091299]; ALS Association; Provost through the University of Arizona