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Related Experiment Videos

Altered proteasomal function in sporadic Parkinson's disease.

Kevin St P McNaught1, Roger Belizaire, Ole Isacson

  • 1Neurodegenerative Disease Research Centre, GKT School of Biomedical Sciences, King's College, London Bridge, London SE1 1UL, UK.

Experimental Neurology
|December 31, 2002
PubMed
Summary

The ubiquitin-proteasome system shows impaired function in Parkinson's disease (PD) brains. This system's failure to clear proteins contributes to neurodegeneration in both sporadic and familial PD.

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Parkinson's disease (PD) involves dopaminergic neuron loss in the substantia nigra pars compacta (SNc).
  • Protein aggregation and inclusions (Lewy bodies) are hallmarks of PD neurodegeneration.
  • Mutations in alpha-synuclein, parkin, and ubiquitin C-terminal hydrolase L1 are linked to familial PD.

Purpose of the Study:

  • To investigate the role of the ubiquitin-proteasome system (UPS) in sporadic Parkinson's disease.
  • To compare proteasome function in the SNc between PD patients and age-matched controls.

Main Methods:

  • Analysis of 26/20S proteasome alpha- and beta-subunit levels in SNc dopaminergic neurons.
  • Assay of 20S proteasomal enzymatic activities in the SNc.

Related Experiment Videos

  • Quantification of proteasome activator (PA700 and PA28) levels in different brain regions.

    • Main Results:

    • Loss of 26/20S proteasome alpha-subunits and impaired enzymatic activity in SNc dopaminergic neurons in sporadic PD.
    • Reduced PA700 proteasome activator levels in the SNc, with increased expression in frontal cortex and striatum.
    • Very low PA28 proteasome activator levels in the SNc in both normal and PD subjects.

    Conclusions:

    • Impaired UPS function, specifically in the SNc, is implicated in the neurodegeneration of sporadic PD.
    • The findings suggest a common mechanism of UPS failure contributing to both sporadic and familial forms of Parkinson's disease.
    • Defective protein degradation by the UPS may underlie the selective vulnerability of SNc neurons in PD.