The Machado–Joseph disease‐associated form of ataxin‐3 impacts dynamics of clathrin‐coated pits

Expansion above a certain threshold in the polyglutamine (polyQ) tract of ataxin‐3 is the main cause of neurodegeneration in Machado–Joseph disease. Ataxin‐3 contains an N‐terminal catalytic domain, called Josephin domain, and a highly aggregation‐prone C‐terminal domain containing the polyQ tract....

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Published in:Cell biology international 2020-05, Vol.44 (5), p.1252-1259
Main Authors: Rosselli‐Murai, Luciana K., Joseph, Jophin G., Lopes‐Cendes, Iscia, Liu, Allen P., Murai, Marcelo J.
Format: Article
Language:English
Subjects:
Ataxin
Ataxin-3 - metabolism
Cell Line
Clathrin
Clathrin - metabolism
clathrin‐coated pits
Coated pits
Coated Pits, Cell-Membrane - metabolism
Endocytosis
expanded ataxin‐3
Humans
Internalization
Machado-Joseph Disease
Neurodegeneration
Peptides - metabolism
Polyglutamine
Protein Aggregation, Pathological
Protein interaction
Repressor Proteins - metabolism
total internal reflection fluorescence microscopy
Transferrin
Trinucleotide repeat diseases
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Summary:Expansion above a certain threshold in the polyglutamine (polyQ) tract of ataxin‐3 is the main cause of neurodegeneration in Machado–Joseph disease. Ataxin‐3 contains an N‐terminal catalytic domain, called Josephin domain, and a highly aggregation‐prone C‐terminal domain containing the polyQ tract. Recent work has shown that protein aggregation inhibits clathrin‐mediated endocytosis (CME). However, the effects of polyQ expansion in ataxin‐3 on CME have not been investigated. We hypothesize that the expansion of the polyQ tract in ataxin‐3 could impact CME. Here, we report that both the wild‐type and the expanded ataxin‐3 reduce transferrin internalization and expanded ataxin‐3 impacts dynamics of clathrin‐coated pits (CCPs) by reducing CCP nucleation and increasing short‐lived abortive CCPs. Since endocytosis plays a central role in regulating receptor uptake and cargo release, our work highlights a potential mechanism linking protein aggregation to cellular dysregulation.
ISSN:1065-6995
1095-8355
DOI:10.1002/cbin.11312