Expert Reviews in Molecular Medicine

 



Review Article

Repeat expansion and autosomal dominant neurodegenerative disorders: consensus and controversy


Dobrila D. Rudnicki a1 and Russell L. Margolis a2c1
a1 Laboratory of Genetic Neurobiology, Department of Psychiatry, Meyer 2-181, 600 N. Wolfe Street, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
a2 Laboratory of Genetic Neurobiology, Departments of Psychiatry and Neurology, Program in Cellular and Molecular Medicine, Meyer 2-181, 600 N. Wolfe Street, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

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.


Key Words: Huntington's disease; trinucleotide; repeat; triplet; neurodegeneration; spinocerebellar; ataxia; polyglutamine; expansion; maturation.

Correspondence:
c1 Laboratory of Genetic Neurobiology, Departments of Psychiatry and Neurology, Program in Cellular and Molecular Medicine, Meyer 2-181, 600 N. Wolfe Street, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Tel: +1 410 614 4262; Fax: +1 410 955 8233; E-mail: rmargoli@jhmi.edu