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polyglutamine repeat diseases

Wednesday 16 July 2003

Classification

- Huntington disease (huntingtin)
- spinocerebellar ataxias

  • SCA1 (ataxin-1)
  • SCA2 (ataxin-2)
  • SCA3 (ataxin-3)
  • SCA6 (CACNA1A)
  • SCA7 (ataxin-7)
  • SCA17 (TAT-BP)

- dentatorubral pallidoluysian atrophy (DRPLA) (atrophin-1)
- spinobulbar muscular atrophy (SBMA) (AR androgen receptor)

Phsyiopathology

Expansion of CAG trinucleotide repeats coding for polyglutamine in unrelated proteins causes at least nine late-onset progressive neurodegenerative disorders, including Huntington’s disease and a number of spinocerebellar ataxias.

Expanded polyglutamine provokes a dominant gain-of-function neurotoxicity, regardless of the specific protein context within which it resides.

Nevertheless, the protein context does modulate polyglutamine toxicity, as evidenced by the distinct clinical and pathological features of the various disorders.

Importantly, polyglutamine toxicity might derive from its ability to aggregate. Indeed, aggregation probably underlies some defining - attributes of the polyglutamine disorders, such as their late onset, progressive nature, and the dependence of onset age on polyglutamine length.

References

- Helmlinger D, Tora L, Devys D. Transcriptional alterations and chromatin remodeling in polyglutamine diseases. Trends Genet. 2006 Oct;22(10):562-70. PMID: 16911843

- Gunawardena S, Goldstein LS. Polyglutamine diseases and transport problems: deadly traffic jams on neuronal highways. Arch Neurol. 2005 Jan;62(1):46-51. PMID: 15642849

- Michalik A, Van Broeckhoven C. Pathogenesis of polyglutamine disorders: aggregation revisited. Hum Mol Genet. 2003 Oct 15;12 Spec No 2:R173-86. PMID: 14504263

- Opal P, Zoghbi HY. The role of chaperones in polyglutamine disease. Trends Mol Med. 2002 May;8(5):232-6. PMID: 12067633

- Taylor JP, Fischbeck KH. Altered acetylation in polyglutamine disease: an opportunity for therapeutic intervention? Trends Mol Med. 2002 May;8(5):195-7. PMID: 12067622

- Gusella JF, MacDonald ME. Molecular genetics: unmasking polyglutamine triggers in neurodegenerative disease. Nat Rev Neurosci. 2000 Nov;1(2):109-15. PMID: 11252773

- Zoghbi HY, Orr HT. Glutamine repeats and neurodegeneration. Annu Rev Neurosci. 2000;23:217-47. PMID: 10845064

- Andrew SE, Goldberg YP, Hayden MR. Rethinking genotype and phenotype correlations in polyglutamine expansion disorders. Hum Mol Genet. 1997 Nov;6(12):2005-10. PMID: 9328463