Ataxin-2 mediated cell death is dependent on domains downstream of the polyQ repeat.
Exp Neurol
; 208(2): 207-15, 2007 Dec.
Article
in En
| MEDLINE
| ID: mdl-17949716
ABSTRACT
Spinocerebellar ataxia 2 (SCA2) belongs to the group of neurodegenerative diseases caused by expansion of a polyglutamine (polyQ) domain. Overexpression of mutant ataxin-2 causes cell death and Golgi dispersion in cell culture as well as morphologic and functional changes in mouse models. To further define the mechanism of ataxin-2 induced cell death, we compared the cytotoxic effects of different domains of normal and mutant ataxin-2. N-terminal truncated ataxin-2(N) with expanded polyQ repeats did not form intranuclear inclusion and was less cytotoxic than the corresponding full-length ataxin-2. Ataxin-2(del42)[Q22], which lacks 42 amino acids (aa) within the Lsm-associated domain (LsmAD) necessary for Golgi localization, showed a diffuse cytoplasmic localization and was more toxic than wild type ataxin-2[Q22]. Mutant ataxin-2(del42)[Q108] displayed the same toxicity as ataxin-2[Q108], but did not disperse the Golgi apparatus to the extent seen with full-length mutant proteins. These observations confirm that ataxin-2 cytotoxicity increases with increasing polyQ expansion and Golgi dispersion and indicate that, in contrast to other polyQ diseases, N-terminal fragments containing the polyQ repeat are less toxic than full-length ataxin-2. Deletion of 42 aa in the Lsm-AD in ataxin-2 results in cytotoxicity without significant abnormalities in the Golgi apparatus. These findings suggest that the C-terminal domains are important for ataxin-2 cytotoxicity and that Golgi abnormalities may not be primary in the pathogenic process.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Peptides
/
COS Cells
/
Trinucleotide Repeat Expansion
/
Mutation
/
Nerve Tissue Proteins
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Exp Neurol
Year:
2007
Document type:
Article
Affiliation country:
Estados Unidos