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Related Experiment Videos

Protein aggregation in motor neurone disorders.

J D Wood1, T P Beaujeux, P J Shaw

  • 1Academic Neurology Unit, Division of Genomic Medicine, University of Sheffield Medical School, Sheffield, UK. J.D.Wood1@Sheffield.ac.uk

Neuropathology and Applied Neurobiology
|November 26, 2003
PubMed
Summary

Protein aggregation is key in X-linked spinobulbar muscular atrophy (SBMA) neurodegeneration. Evidence for protein aggregation in amyotrophic lateral sclerosis (ALS) is less clear, hindering therapeutic development for this motor neuron disease.

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Abnormal protein folding and aggregation are leading hypotheses for neurodegeneration.
  • This review focuses on X-linked spinobulbar muscular atrophy (SBMA) and amyotrophic lateral sclerosis (ALS), particularly SOD1-linked familial ALS.
  • Understanding these mechanisms is crucial for developing effective treatments for motor neuron diseases.

Purpose of the Study:

  • To comparatively review experimental and human tissue evidence for protein aggregation in SBMA and ALS.
  • To elucidate the role of protein aggregation in neuronal death in these motor system disorders.
  • To identify potential therapeutic targets by examining the biochemical pathways involved.

Main Methods:

  • Review of experimental data from transgenic mouse, Drosophila, and cell culture models of SBMA.

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  • Analysis of human tissue-based evidence for protein aggregation in SBMA and ALS.
  • Examination of downstream biochemical events, including gene transcription pathways and chaperone systems.

    • Main Results:

    • Protein aggregation of the mutated androgen receptor is an obligate mechanism in SBMA models, linked to CREB-binding protein and chaperone systems.
    • Evidence for protein aggregation in SOD1-linked familial ALS models is less conclusive, with unclear roles for ubiquitinated inclusions.
    • While some experimental data suggest mutant SOD1 aggregation contributes to mitochondrial dysfunction and apoptosis, human tissue evidence is inconsistent.

    Conclusions:

    • Protein aggregation is a well-established mechanism in SBMA, offering potential therapeutic targets.
    • The role of protein aggregation in ALS pathogenesis, especially SOD1-linked forms, requires further elucidation.
    • Further research into the biochemical basis of inclusions and mutant SOD1 oligomers is needed for ALS therapeutic strategies.