Polyglutamine diseases: the special case of ataxin-3 and Machado-Joseph disease

Prog Neurobiol. 2011 Sep 15;95(1):26-48. doi: 10.1016/j.pneurobio.2011.06.007. Epub 2011 Jun 28.


Polyglutamine (polyQ) diseases are a group of nine neurodegenerative disorders caused by an unstable CAG expansion in the codifying region of their respective associated genes. However, each polyQ disease displays a different symptomatic and pathoanatomic profile and the proteins involved share no homology outside the polyQ tract. This suggests that the other regions of the proteins and the cellular functions they mediate are important in defining disease progression and specificity. Machado-Joseph disease (MJD), the most common form of spinocerebellar ataxia worldwide, is a progressive and ultimately fatal neurodegenerative disorder caused by polyQ expansion in ataxin-3 (atx3), a conserved and ubiquitous protein known to bind polyubiquitin chains and to function as a deubiquitinating enzyme. Atx3 has been linked to protein homeostasis maintenance, transcription, cytoskeleton regulation and myogenesis, but its precise biologic function remains a mystery, limiting the understanding of the mechanisms by which the mutated protein leads to the selective neuronal death profile observed in MJD patients. A number of recent evidence support the idea that the toxic entities behind neuronal demise may be either the dysfunctional expanded atx3 or the soluble amyloid-like oligomers formed by self-assembly of the aggregation-prone mutated protein. Expanded atx3 pathogenicity is likely the result of a series of events implicating both atx3 dysfunction and aggregation, possibly involving both full-length atx3 and polyQ-containing fragments that may act as seeds for protein aggregation. A deeper understanding of polyQ protein biology, the way the expansion alters their features, and the consequences of these changes for cell functioning and survival are sure to be of critical importance for developing future treatment of polyQ diseases.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Ataxin-3
  • Cell Death
  • Disease Models, Animal
  • Humans
  • Machado-Joseph Disease / genetics*
  • Machado-Joseph Disease / pathology*
  • Machado-Joseph Disease / physiopathology*
  • Models, Biological
  • Models, Molecular
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neurons / cytology
  • Neurons / physiology
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Peptides*
  • Protein Conformation
  • Repressor Proteins / chemistry
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*


  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Peptides
  • Repressor Proteins
  • polyglutamine
  • ATXN3 protein, human
  • Ataxin-3