Ataxin-2 mediated cell death is dependent on domains downstream of the polyQ repeat.
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.
Ng
Hiushan
H
Rose Moss Laboratory for Parkinson and Neurodegenerative Diseases, Burns and Allen Research Institute, and Division of Neurology, Cedars-Sinai Medical Center, USA.
Pulst
Stefan-M
SM
Huynh
Duong P
DP
D000595:Amino Acid Sequence; D000818:Animals; D000067528:Ataxins; D019556:COS Cells / Q000378:metabolism / Q000502:physiology*; D016923:Cell Death; D002470:Cell Survival; D002522:Chlorocebus aethiops; D006056:Golgi Apparatus / Q000378:metabolism / Q000648:ultrastructure; D009154:Mutation / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D010446:Peptide Fragments / Q000235:genetics / Q000502:physiology; D010455:Peptides / Q000235:genetics*; D017434:Protein Structure, Tertiary / Q000502:physiology; D017384:Sequence Deletion; D014162:Transfection; D019680:Trinucleotide Repeat Expansion; D015854:Up-Regulation; D021601:trans-Golgi Network / Q000378:metabolism
D000067528:Ataxins; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D010455:Peptides; C097188:polyglutamine