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Calpain-mediated proteolysis as driver and modulator of polyglutamine toxicity

Rana Dilara Incebacak Eltemur1,2, Huu Phuc Nguyen1, Jonasz Jeremiasz Weber1,2

  • 1Department of Human Genetics, Ruhr University Bochum, Bochum, Germany.

Frontiers in Molecular Neuroscience
|November 17, 2022
PubMed

Insights

Calpains, or calcium-activated proteases, generate toxic protein fragments in neurodegenerative diseases like Huntington's. Targeting calpain activity offers a promising therapeutic strategy for these conditions.

Area of Science:

  • Molecular Biology
  • Neuroscience
  • Biochemistry

Background:

  • Posttranslational modifications, particularly proteolytic processes, significantly impact protein integrity and cellular function.
  • Calcium-activated proteases, known as calpains, act as modulator proteases with limited proteolytic activity, altering substrate structure and function.
  • Proteolytic events, including those mediated by calpains, are implicated in the pathogenesis of neurodegenerative disorders, notably polyglutamine diseases.

Purpose of the Study:

  • To review the role of calpains in proteolytic processes within the context of polyglutamine disorders.
  • To explore the concept of 'toxic fragments' and their generation by calpains in neurodegeneration.
  • To highlight calpains as potential therapeutic targets for Huntington disease and Machado Joseph disease.

Main Methods:

  • Literature review focusing on calpain function, proteolytic processes, and polyglutamine disorders.
  • Analysis of findings related to the 'toxic fragment hypothesis' in neurodegeneration.
  • Synthesis of current knowledge on calpain-mediated proteolysis in Huntington disease and Machado Joseph disease.

Main Results:

  • Calpains play a key role in generating harmful protein breakdown products (toxic fragments) in polyglutamine disorders.
  • The 'toxic fragment hypothesis' posits that these fragments contribute significantly to the molecular pathogenesis of these diseases.
  • Calpains are identified as critical players and potential therapeutic targets in Huntington disease and Machado Joseph disease.

Conclusions:

  • Calpain-mediated proteolysis is a significant posttranslational mechanism contributing to neurodegeneration.
  • Understanding calpain's role in generating toxic fragments is crucial for developing effective treatments.
  • Further research into calpain-mediated proteolysis could lead to unifying therapeutic strategies for polyglutamine disorders and other neurodegenerative conditions.
Keywords:
Huntington disease (HD)calpainsdentatorubral-pallidoluysian atrophy (DRPLA)posttranslational modifications (PTMs)proteolytic cleavagespinal and bulbar muscular atrophy (SBMA)spinocerebellar ataxia (SCA)toxic fragments

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