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 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.

Nyckelord

Adult

Brain/metabolism/*pathology

Caspase 3

Caspases/metabolism

Cell Line

Cell Nucleus/metabolism

Child

Cysteine Endopeptidases/metabolism

Enzyme Activation

Green Fluorescent Proteins

Heat-Shock Proteins/metabolism

Humans

Inclusion Bodies/metabolism/ultrastructure

Luminescent Proteins/genetics/metabolism

Microscopy; Confocal

Microscopy; Electron

Middle Aged

Multienzyme Complexes/metabolism

Mutation

Nerve Tissue Proteins/genetics/metabolism

Neurons/metabolism

Nuclear Proteins

Proteasome Endopeptidase Complex

Recombinant Fusion Proteins/genetics/metabolism

Repressor Proteins

Spinocerebellar Ataxias/genetics/metabolism/*pathology

Temporal Lobe/metabolism/pathology

Tumor Cells; Cultured

MEDICINE

MEDICIN

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