Proteolytic cleavage has been implicated in the pathogenesis of diverse neurodegenerative diseases
involving abnormal protein accumulation. Polyglutamine diseases are a group of nine hereditary disorders caused
by an abnormal expansion of repeated glutamine tracts contained in otherwise unrelated proteins. When expanded,
these proteins display toxic properties and are prone to aggregate, but the mechanisms responsible for the
selective neurodegeneration observed in polyglutamine disease patients are still poorly understood. It has been
suggested that the neuronal toxicity of polyglutamine-expanded proteins is associated with the production of
deleterious protein fragments.
This review aims at discussing the involvement of proteolytic cleavage in the six types of spinocerebellar ataxia
caused by polyglutamine expansion of proteins. The analysis takes into detailed consideration evidence concerning
fragment detection and the mechanisms of fragment toxicity.
Current evidence suggests that the proteins involved in spinocerebellar ataxia types 3, 6 and 7 give rise to stable
proteolytic fragments. Fragments carrying polyglutamine expansions display increased tendency to aggregate and
toxicity, comparing with their non-expanded counterparts or with the correspondent full-length expanded proteins.
Data concerning spinocerebellar ataxia types 1, 2 and 17 is still scarce, but available results afford further
Available literature suggests that proteolytic cleavage of expanded polyglutamine-containing proteins enhances
toxicity in disease-associated contexts and may constitute an important step in the pathogenic cascade of polyglutamine
diseases. Countering protein fragmentation thus presents itself as a promising therapeutic aim.