Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 May;44(5):1252-1259.
doi: 10.1002/cbin.11312. Epub 2020 Feb 11.

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

Luciana K Rosselli-Murai  1   2 , Jophin G Joseph  2 , Iscia Lopes-Cendes  3   4 , Allen P Liu  2 , Marcelo J Murai  1   3
Affiliations

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

Luciana K Rosselli-Murai et al. Cell Biol Int. 2020 May.

Abstract

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.

Keywords: Machado-Joseph disease; clathrin-coated pits; expanded ataxin-3; total internal reflection fluorescence microscopy.

PubMed Disclaimer

References

    1. Aguet F, Antonescu CN, Mettlen M, Schmid SL, Danuser G (2013) Advances in analysis of low signal-to-noise images link dynamin and AP2 to the functions of an endocytic checkpoint. Dev Cell 26: 279-91. https://doi.org/10.1016/j.devcel.2013.06.019
    1. Arrasate M, Mitra S, Schweitzer ES, Segal MR, Finkbeiner S (2004) Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 431: 805-10. https://doi.org/10.1038/nature02998
    1. Chen S, Berthelier V, Hamilton JB, O'Nuallain B, Wetzel R (2002) Amyloid-like features of polyglutamine aggregates and their assembly kinetics. Biochemistry 41: 7391-9.
    1. Cocucci E, Aguet F, Boulant S, Kirchhausen T (2012) The first five seconds in the life of a clathrin-coated pit. Cell 150: 495-507. https://doi.org/10.1016/j.cell.2012.05.047
    1. Contessotto MGG, Rosselli-Murai LK, Garcia MCC, Oliveira CLP, Torriani IL, Lopes-Cendes I, Murai MJ (2018) The Machado-Joseph disease-associated expanded form of ataxin-3: overexpression, purification, and preliminary biophysical and structural characterization. Protein Expr Purif 152: 40-5. https://doi.org/10.1016/j.pep.2018.07.005

LinkOut - more resources