Similarities between spinocerebellar ataxia type 7 (SCA7) cell models and human brain: proteins recruited in inclusions and activation of caspase-3

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 SCA 7 are unknown. We have established SCA7 cell culture models in HEK293 and S H-SY5Y cells, in order to analyse the effects of overexpression of the muta nt ataxin-7 protein. The cells readily formed anti-ataxin-7 positive, fibri llar inclusions and small, nuclear electron dense structures. We have compa red the inclusions in cells expressing mutant ataxin-7 and in human SCA7 br ain 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 casp ase-3 was recruited into the inclusions in both the cell models and human S CA7 brain and its expression was upregulated in cortical neurones, suggesti ng that it may play a role in the disease process. Finally, on the ultrastr uctural level, there were signs of autophagy and nuclear indentations, indi cative of a major stress response in cells expressing mutant ataxin-7.