Vol 3 n° 1 - Genetic Approach to Neuropsychiatric Disorders
Past issues Contributors How to publish Contributions and comments Home
 
Huntington’s disease (HD) is a progressive, late-onset neu- rodegenerative illness with autosomal dominant inheri- tance that affects one in 10 000 individuals in Western Europe. The disease is caused by a polyglutamine repeat expansion located in the N-terminal region of the hunt- ingtin protein. The mutation is likely to act by a gain of function, but the molecular mechanisms by which it leads to neuronal dysfunction and cell death are not yet known. The normal function of huntingtin in cell metabolism is also unclear. There is no therapy for HD. Research on HD should help elucidate the pathogenetic mechanism of this illness in order to develop successful treatments to prevent or slow down symptoms. This article presents new results in HD research focusing on in vivo and in vitro model sys- tems, potential molecular mechanisms of HD, and the development of therapeutic strategies. A growing number of neurodegenerative disor- ders have been found to belong to the group of CAG triplet repeat disorders, including Huntington’s disease (HD), spinal and bulbar muscular atrophy (SBMA), dentatorubral palidoluysian atrophy, Machado-Joseph disease/spinocerebellar ataxia type 3, and spinocerebel- lar ataxias types 1, 2, 6, and 7.1 All these illnesses are caused by an elongated CAG repeat located in the cod- ing region of the respective genes, which is translated into a polyglutamine tract. The mechanism by which CAG repeats elongate is currently unknown and is the subject of intensive investigation.2 Characteristic features of CAG repeat disorders are autosomal dominant inheritance (except SBMA), late onset, selective neurodegeneration, genetic anticipation, a pathological threshold at which the mutation becomes virulent,  and  an  inverse  correlation  between  CAG repeat length and age at disease onset. The number of glutamines in the normal (<35 residues) and abnormal ranges (>35 residues) are similar in each disease pro- tein, with the exception of spinocerebellar ataxia type 6 (SCA6). The disease proteins show no homology with each other except the glutamine repeat, suggesting that the elongated glutamine tract confers a toxic gain of function to each disease protein. The current body of evidence supports the hypothesis that expanded poly- glutamine repeats undergo a conformational change leading to abnormal protein–protein interactions, mul- timerization, and  the  formation  of  insoluble  protein aggregates.3-5 Indeed, abnormal neuronal inclusions have been detected in the brains of patients.6,7 Although the causal relationship between aggregate formation and disease remains to be proven, the gradual deposition of disease protein in neurons is consistent with the late onset and progressive nature of symptoms. Furthermore, the process of aggregate formation is ultimately associ- ated with degeneration of mammalian cells.8 Analysis of  in  vitro  and  in  vivo  model  systems  support  the hypothesis   that   glutamine   repeat   disorders,   like Alzheimer’s disease and Parkinson’s disease, are caused by an aggregation-based pathogenetic mechanism. How- ever, there are also studies that suggest that the process of aggregate formation may even be beneficial to neu- Huntington’s disease: from gene to potential therapy Hans Lehrach, PhD; Erich E. Wanker, PhD Keywords: aggregation; fibrillogenesis; Huntington’s disease; neurodegenera-tion; polyglutamine

Author affiliations: Max-Planck-Institut für Molekulare Genetik, Berlin (Dahlem), Germany Address for correspondence:  Max-Planck-Institut für Molekulare Genetik (Max-Planck Institute for Molecular Genetics), Ihnestraße 73, D-14195 Berlin, Germany
(e-mail: lehrach@molgen.mpg.de) 1 7 B a s i c   r e s e a r c h