February, 2006- Huntington's disease (HD) is a devastating age-related neurological illness, affecting approximately, 1 in every 10,000 people, and whose symptoms include severe behavioral and emotional disturbances and severe cognitive impairment. HD is a familial disease that is passed from parent to child through a mutation in the normal gene. Each child of an HD parent has a 50-50 chance of inheriting the HD gene. The duration of the disease usually lasts for ~15-20 years, ultimately resulting in death. Currently, there is no effective way to prevent or cure HD. Recently, MBC researchers, headed by Dr. Mervyn Monteiro , discovered a new approach to understanding Huntington's disease, which may lead to new therapies for this disease.

HD is caused by an abnormal expansion of a trinucleotide sequence (CAG) in the gene encoding the huntingtin (htt) protein. Since CAG encodes the amino acid glutamine, the resulting protein has too many glutamine repeats (polyglutamine). The exact mechanism by which expanded polyglutamine tracts cause disease is not understood. Interestingly, however, proteins with longer polyglutamine repeats are more prone to aggregate, and it is believed that these aggregates may be toxic.

Figure 1: Animal Model of Huntington's Disease. C. elegans shows that labeled ubiquilin (RFP-UBQLN) co-localizes with fluorescently labeled htt (GFP-htt).

Dr. Monteiro, an investigator at the MBC, became interested in the possibility that ubiquilin, a protein his group had identified as an interactor of presenilins, mutations in which cause Alzheimer's disease, might be involved in regulating HD pathogenesis because ubiquilin proteins were reported to bind to expanded polyglutamine proteins. In a recently published paper, Dr. Monteiro and his colleagues showed that when ubiquilin was overexpressed in an animal model of HD, the animals no longer showed the motility defects associated with HD. They also showed that ubiquilin could reduce polyglutamine protein aggregation and cell death, in a HeLa cell line expressing htt, in a dose dependent manner.

Figure 2: Ubiquilin protects htt cell lines from serum deprivation-induced cell death. Pink/red and dark blue indicated dying cells; green are healthy cells.

Dr. Monteiro says, Our finding is exciting because it raises the possibility that methods to modulate ubiquilin expression in humans may provide a novel therapeutic opportunity to treat Huntington's disease and other related polyglutamine disorders.

To date, at least eight other neurological disorders are associated with an expansion of polyglutamine tracts; these disorders include dentatorubral-palidoluysian atrophy, spinal and bulbar muscular atrophy, and spinocerebella ataxias 1, 2, 3, 6, 7 and 17. Thus polyglutamine expansion causes several human neurological disorders, all of which may benefit from Dr. Monteiro's research.

Hongmin Wang, Precious J. Lim, Chaobo Yin, Matthias Rieckher, Bruce E. Vogel, and Mervyn J. Monteiro. Suppression of Polyglutamine-Induced Toxicity in Cell and Animal Models of Huntington's Disease by Ubiquilin. Human Molecular Genetics Advance Access published on February 6, 2006. doi:10.1093/hmg/ddl017 [Abstract] [Accepted Manuscript]