Similarities between spinocerebellar ataxia type 7 (SCA7) cell models and human brain: proteins recruited in inclusions and activation of caspase-3.
Human Molecular Genetics. 2001-10-01; 10(22): 2569-2579
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1. Hum Mol Genet. 2001 Oct 15;10(22):2569-79.
Similarities between spinocerebellar ataxia type 7 (SCA7) cell models and human
brain: proteins recruited in inclusions and activation of caspase-3.
Zander C(1), Takahashi J, El Hachimi KH, Fujigasaki H, Albanese V, Lebre AS,
Stevanin G, Duyckaerts C, Brice A.
(1)INSERM U289, Hôpital de la Salpêtrière, 47 boulevard de l’Hôpital, 75651
Paris, Cedex 13, France.
Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant polyglutamine
disorder presenting with progressive cerebellar ataxia and blindness. The
molecular mechanisms underlying the selective neuronal death typical of SCA7 are
unknown. We have established SCA7 cell culture models in HEK293 and SH-SY5Y
cells, in order to analyse the effects of overexpression of the mutant ataxin-7
protein. The cells readily formed anti-ataxin-7 positive, fibrillar inclusions
and small, nuclear electron dense structures. We have compared the inclusions in
cells expressing mutant ataxin-7 and in human SCA7 brain tissue. There were
consistent signs of ongoing abnormal protein folding, including the recruitment
of heat-shock proteins and proteasome subunits. Occasionally, sequestered
transcription factors were found. Activated caspase-3 was recruited into the
inclusions in both the cell models and human SCA7 brain and its expression was
upregulated in cortical neurones, suggesting that it may play a role in the
disease process. Finally, on the ultrastructural level, there were signs of
autophagy and nuclear indentations, indicative of a major stress response in
cells expressing mutant ataxin-7.
PMID: 11709544 [Indexed for MEDLINE]