Pathogenesis of Polyglutamine Diseases

Maria Pennuto, Italian Institute of Technology, Genova, Italy
Fabio Sambataro, Italian Institute of Technology, Parma, Italy

Published online: December 2010

DOI: 10.1002/9780470015902.a0021486

Polyglutamine (polyQ) diseases are neurodegenerative disorders caused by expansion in specific genes of a trinucleotide repeat, cytosine–adenine–guanine (CAG), which encodes glutamine. In 1991, CAG repeat expansion in the androgen receptor was linked to spinal and bulbar muscular atrophy (SBMA), thus indicating for the first time a causative role of polyQ expansion in neurodegenerative disorders. Subsequently, polyQ expansions in eight other genes were shown to be responsible for different neurodegenerative diseases, including Huntington disease, dentatorubral-pallidoluysian atrophy and six types of spinocerebellar ataxia. PolyQ diseases share several features, such as the phenomenon of genetic anticipation, and that to be late-onset and progressive disorders. Despite these and other common features, specific populations of neurons are vulnerable in each disease. Approximately 20 years after the discovery of expanded polyQ as a leading cause of neurodegeneration, why selective neuronal populations degenerate in each disorder is still an enigma.

Key Concepts:

  • Polyglutamine diseases are a family of late onset, genetically inherited neurodegenerative disorders.
  • Polyglutamine diseases are caused by expansion of the CAG trinucleotide repeat encoding glutamine in nine different genes.
  • Expansion of polyglutamine confers a novel, toxic gain of function to the mutant protein.
  • The length of the polyglutamine tract correlates with disease onset and dictates disease severity.
  • Polyglutamine proteins are ubiquitous. None the less, expansion of polyglutamine tracts causes selective neuronal dysfunction and degeneration.
  • Specific populations of neurons degenerate in each polyglutamine disease, giving rise to different clinical disease manifestations.

Keywords: polyglutamine disease; neurodegeneration; gain and loss of function; aggregate/inclusions; Huntington disease; spinocerebellar ataxia; Kennedy disease; dentatorubral-pallidoluysian atrophy

Figure 1. Polyglutamine (polyQ) diseases. PolyQ diseases are a family of nine neurodegenerative disorders, which includes Huntington disease (HD), dentatorubral-pallidoluysian atrophy (DRPLA), spinal and bulbar muscular atrophy (SBMA) and six types of spinocerebellar ataxia (SCA). Although polyQ diseases are caused by the same mutation, expansion of a polyQ tract in the coding region of nine different genes, specific populations of neurons degenerate in each disease, such as striatal and cortical neurons in HD, dentate nucleus of the cerebellum and pallidum in DRPLA, lower motor neurons in SBMA and Purkinje cells in SCAs.
Figure 2. Pathogenic pathways in polyglutamine (polyQ) diseases. PolyQ expansion affects several cellular processes. PolyQ proteins accumulate in the nucleus and alter gene expression. PolyQ proteins alter mitochondrial function and cell metabolism. PolyQ proteins are degraded by the ubiquitin-proteasome system and autophagy. Interaction of the polyQ proteins with the cellular protein degradation machinery may hamper its function, thereby altering cellular homeostasis. PolyQ proteins are not properly folded and accumulate in the cells in forms of aggregates and inclusions. PolyQ proteins alter fast axonal transport and synaptic transmission.
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Related Sub-Topics:

Neurobiology of Disease | Mutational Mechanisms of Genetic Disease | Statistical Methodology in Genetics
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Article Title: Pathogenesis of Polyglutamine Diseases
 
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Pennuto, Maria, and Sambataro, Fabio(Dec 2010) Pathogenesis of Polyglutamine Diseases. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021486]