A team of scientists led by Professor Mervyn J. Monteiro at UMBI's Medical Biotechnology Center has published a paper in Human Molecular Genetics (PMID: 19039036; 2008 Nov 27. Epub ahead of print) providing important insights into Huntington's disease.

The paper, titled "Effects of overexpression of huntingtin proteins on mitochondrial integrity" is authored by Hongmin Wang, Precious J. Lim, Mariusz Karbowski and Mervyn J. Monteiro.

Huntington's disease affects about 1 in every 10,000 people in the United States: it is associated with severe behavioral and emotional disturbances, severe cognitive impairment, and decreased life expectancy. HD is caused by inheritance of a mutation in a gene calledhuntingtin (htt), which contains a CAG trinucleotide repeat that is translated into a glutamine amino acid that is reiterated many times. In people affected with HD the polyglutamine tract increases beyond 35 repeats, whereas those who are unaffected have less than 35 repeats.

UMBI investigators examined the effects of expression of fluorescently-tagged htt proteins containing different lengths of polyglutamine tracts on the integrity of mitochondria, the organelle that produces the main energy source of cells. They found that expression of htt proteins with expanded polyglutamine repeats (74 or 138 repeats) were more sensitized to oxidative stress-induced mitochondrial fragmentation and cell death, which correlated with reduced energy (ATP) production, than cells expressing htt proteins containing a normal range of polyglutamine repeats (17 or 28 repeats). By live cell imaging they showed that mitochondria in cells expressing expanded polyglutamine proteins showed decreased movement and fusion.Furthermore, they found that expression of cDNAs encoding proteins that stimulate mitochondria fusion can reduce both fragmentation and toxicity of htt proteins containing expanded polyglutamine repeats.

These results provide important insights into the mechanisms of pathogenesis of Huntington's disease. An understanding of the effects of expanded polyglutamine tracts on mitochondria may prove critical in development of treatments for Huntington's disease. In addition, because eight other neurological disorders are associated with expansions of polyglutamine tracts, the lessons learnt from this study might equally apply to development of treatments for the other polyglutamine disorders.