Pathogenesis of Polyglutamine Diseases


Polyglutamine (polyQ) diseases are inherited neurodegenerative disorders caused by expansions in the distinct genes harbouring a (cytosine‐adenine‐guanine) CAG‐trinucleotide repeat, which is translated into an expanded polyQ tract within the encoded protein. This induces toxic protein aggregates, which eventually causes neurodegeneration and the spreading of pathology. Nine polyQ diseases have been reported so far; spinal and bulbar muscular atrophy, the first identified polyQ disease in 1991, followed by Huntington disease, dentatorubral–pallidoluysian atrophy and six types of spinocerebellar ataxia. PolyQ diseases elicit common phenotypes of late‐onset, progressive neurodegeneration and the presence of intracellular aggregates, especially in the affected neurons. In addition, toxic roles of expanded repeat‐containing RNAs are implicated as the additional mechanisms of polyQ diseases. Nearly 30 years since the discovery of expanded CAG repeats as a cause of neurodegeneration, the mechanism of vulnerability of specific neuronal populations still remains an enigma.

Key Concepts

  • Polyglutamine diseases are late‐onset, inherited neurodegenerative disorders, caused by expansions of a CAG‐trinucleotide repeat encoding glutamine in nine distinct genes.
  • CAG expansions confer a gain‐of‐function toxicity, occasionally with a concomitant loss or augmentation of function of a native protein.
  • The repeat length of polymorphic CAG trinucleotides is correlated with disease severity and age of onset.
  • Despite the ubiquitous expression of the mutated genes, CAG‐expansion mutations cause dysfunction and degeneration in specific neuronal subpopulations and present a great diversity of clinical disease manifestations.
  • Toxic repeat‐expanded RNAs and transneuronal propagation of pathogenic proteins would also play a role in the specific pathogenesis of polyglutamine diseases.

Keywords: polyglutamine disease; neurodegeneration; gain and loss of function; protein aggregation; RNA toxicity

Figure 1. The mechanism of pathogenesis of polyglutamine (polyQ) diseases. Expanded polyQ tracts and CUG‐expanded RNAs dysregulate diverse cellular processes, principally caused by their intracellular accumulation. The pathology potentially propagates via an extracellular vesicle‐mediated transneuronal transfer of polyQ aggregates.


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Sahashi, Kentaro, and Katsuno, Masahisa(Oct 2018) Pathogenesis of Polyglutamine Diseases. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0021486.pub2]