Proteolytic Cleavage of Polyglutamine Disease-Causing Proteins: Revisiting the Toxic Fragment Hypothesis

Curr Pharm Des. 2017;23(5):753-775. doi: 10.2174/1381612822666161227121912.


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 investigation. 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.

Keywords: Neurodegenerative diseases; ataxin-3; ataxin-7; machado-joseph disease; polyglutamine diseases; proteolytic cleavage; spinocerebellar ataxia; toxic fragments; voltage-dependent P/Q-type calcium channel subunit alpha-1A.

Publication types

  • Review

MeSH terms

  • Animals
  • Humans
  • Nerve Tissue Proteins / metabolism*
  • Neurodegenerative Diseases / etiology*
  • Neurodegenerative Diseases / metabolism
  • Neurodegenerative Diseases / pathology
  • Peptide Hydrolases / metabolism*
  • Peptides / chemistry
  • Peptides / metabolism*
  • Peptides / toxicity
  • Proteolysis


  • Nerve Tissue Proteins
  • Peptides
  • polyglutamine
  • Peptide Hydrolases