Repeat expansion and autosomal dominant neurodegenerative disorders: Consensus and controversy

Dobrila D. Rudnicki, Russell Louis Margolis

Research output: Contribution to journalArticle

Abstract

Repeat-expansion mutations cause 13 autosomal dominant neurodegenerative disorders falling into three groups. Huntington's disease (HD), dentatorubral pallidoluysian atrophy (DRPLA), spinal and bulbar muscular atrophy (SBMA), and spinocerebellar ataxias (SCAs) types 1, 2, 3, 7 and 17 are each caused by a CAG repeat expansion that encodes polyglutamine. Convergent lines of evidence demonstrate that neurodegeneration in these diseases is a consequence of the neurotoxic effects of abnormally long stretches of glutamines. How polyglutamine induces neurodegeneration, and why neurodegeneration occurs in only select neuronal populations, remains a matter of intense investigation. SCA6 is caused by a CAG repeat expansion in CACNA1A, a gene that encodes a subunit of the P/Q-type calcium channel. The threshold length at which the repeat causes disease is much shorter than in the other polyglutamine diseases, and neurodegeneration may arise from expansion-induced change of function in the calcium channel. Huntington's disease-like 2 (HDL2) and SCAs 8, 10 and 12 are rare disorders in which the repeats (CAG, CTG or ATTCT) are not in protein-coding regions. Investigation into these diseases is still at an early stage, but it is now reasonable to hypothesise that the net effect of each expansion is to alter gene expression. The different pathogenic mechanisms in these three groups of diseases have important implications for the development of rational therapeutics.

Original languageEnglish (US)
Pages (from-to)1-24
Number of pages24
JournalExpert Reviews in Molecular Medicine
Volume5
Issue number21
DOIs
StatePublished - Aug 22 2003

Fingerprint

Neurodegenerative Diseases
Consensus
Spinocerebellar Ataxias
Q-Type Calcium Channels
P-Type Calcium Channels
Progressive Myoclonic Epilepsy
Atrophic Muscular Disorders
Huntington Disease
Calcium Channels
Glutamine
Open Reading Frames
Gene expression
Gene Expression
Mutation
Genes
Population
polyglutamine
Proteins
Therapeutics

Keywords

  • ataxia
  • expansion
  • Huntington's disease
  • maturation
  • neurodegeneration
  • polyglutamine
  • repeat
  • spinocerebellar
  • trinucleotide
  • triplet

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Repeat expansion and autosomal dominant neurodegenerative disorders : Consensus and controversy. / Rudnicki, Dobrila D.; Margolis, Russell Louis.

In: Expert Reviews in Molecular Medicine, Vol. 5, No. 21, 22.08.2003, p. 1-24.

Research output: Contribution to journalArticle

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