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 language | English (US) |
---|---|
Pages (from-to) | 362-369 |
Number of pages | 8 |
Journal | Neurobiology of Disease |
Volume | 27 |
Issue number | 3 |
DOIs | |
State | Published - Sep 2007 |
Keywords
- Ataxin-3
- Cleavage fragment
- Machado-Joseph disease
- Polyglutamine disease
- Proteolysis
- Spinocerebellar ataxia type 3
- Transgenic mouse
ASJC Scopus subject areas
- Neurology