Researchers from the MassGeneral Institute for Neurodegenerative Disease (MIND) have identified a possible mechanism underlying how the gene mutation that causes Huntington's disease (HD) leads to the degeneration and death of brain cells. In the Oct. 6 issue of Cell, they show that the abnormal form of the huntingtin protein, the product of the HD gene mutation, interferes with the production of a protein critical to cellular energy metabolism. The discovery is the first to bring together two processes believed to be involved in the pathology of HD the conversion of genetic information into proteins and the production of energy within cells.
"Our study indicates that these two pathogenic mechanisms are linked, in that disruption of gene transcription by mutant huntingtin leads to abnormal energy metabolism, which affects energy-dependent cellular processes and results in neurodegeneration," says Dimitri Krainc, MD, PhD, of MIND and the MGH Department of Neurology, who led the research team. "The role of mitochondria [subcellular structures that produce the cells' energy] in the process of nerve cell dysfunction and death is an emerging theme in neurodegenerative disorders, but the mechanism behind HD has been elusive."
HD causes the degeneration and death of cells in the basal ganglia an area deep within the brain particularly in a structure called the striatum. Although the precise function of the huntingtin protein is still unknown, recent studies have suggested that the mutant form directly interferes with transcription of neuronal genes. Evidence also has pointed to disruptions in cellular energy metabolism as key factors in HD. As a result, the MIND team focused on a protein called PGC-1a, which is known to regulate energy in cells throughout the body. Their previous research had shown that mice in which the PGC-1a gene had been knocked out developed brain lesions in the striatum.