A Mutant ataxin-3 fragment results from processing at a site N-terminal to amino acid 190 in brain of Machado-Joseph disease-like transgenic mice

Veronica F. Colomer Gould, Daniel Goti, Donna Pearce, Guillermo A. Gonzalez, Hong Gao, Mario Bermudez de Leon, Nancy A. Jenkins, Neal G. Copeland, Christopher A. Ross, Dale R. Brown

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41 Citations (Scopus)

Abstract

Machado-Joseph disease also called spinocerebellar ataxia type 3 (MJD/SCA3) is a hereditary and neurodegenerative movement disorder caused by ataxin-3 with a polyglutamine expansion (mutant ataxin-3). Neuronal loss in MJD/SCA3 is associated with a mutant ataxin-3 toxic fragment. Defining mutant ataxin-3 proteolytic site(s) could facilitate the identification of the corresponding enzyme(s). Previously, we reported a mutant ataxin-3 mjd1a fragment in the brain of transgenic mice (Q71) that contained epitopes C-terminal to amino acid 220. In this study, we generated and characterized neuroblastoma cells and transgenic mice expressing mutant ataxin-3 mjd1a lacking amino acids 190-220 (deltaQ71). Less deltaQ71 than Q71 fragments were detected in the cell but not mouse model. The transgenic mice developed an MJD/SCA3-like phenotype and their brain homogenates had a fragment containing epitopes C-terminal to amino acid 220. Our results support the toxic fragment hypothesis and narrow the mutant ataxin-3 cleavage site to the N-terminus of amino acid 190.

Original languageEnglish
Pages (from-to)362-369
Number of pages8
JournalNeurobiology of Disease
Volume27
Issue number3
DOIs
Publication statusPublished - 1 Sep 2007
Externally publishedYes

Bibliographical note

Funding Information:
We especially thank: (a) Debbie Swing for performing the zygote injections; (b) Mrs. Mary Keyser and Suzanne Fowble for budget administration; and (c) Dr. Pamela Talalay for critical editing of the manuscript. This work was supported by: (a) Donation from JCG (VCG); (b) NIH grant NS42731-01 (VCG); (c) AHA grant EIG 0140166N (VCG); and in part by (d) NIH Intramural Research Program, National Cancer Institute, Center for Cancer Research (NAJ, NGC).

Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.

All Science Journal Classification (ASJC) codes

  • Neurology

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