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.
To investigate the possible effect of the HD mutation on PGC-1a, the researchers first examined brain tissue samples from presymptomatic HD patients and found that levels of the protein were significantly reduced in the portion of the striatum first affected by the disorder. Examination of the brains of PGC-1a knockout mice found decreased activity in metabolic pathways known to be involved in mitochondrial function – pathways also downregulated in human HD – and brain samples from HD patients also showed reduced expression of mitochondrial genes.
Within the striatum HD causes degeneration of medium spiny neurons, the most common cells within the structure. The reseachers found that PGC-1a levels in those particular neurons were much lower among mice with the HD mutation than in normal mice. In contrast, levels of the protein were dramatically higher in striatal cells not affected by HD, suggesting that PGC-1a may protect against neurodegeneration. Analysis of striatal cells from the HD mice also showed significant underexpression of both PGC-1a and key mitochondrial genes, further linking decreased protein levels with deficits in energy metabolism.
Additional experiments indicated that mutant huntingtin interferes with the production of PGC-1a by occupying the regulatory region of the PGC-1a gene and inhibiting its transcription. Delivery of a viral vector expressing PGC-1a into the striatum of mice with the HD mutation resulted in significantly less degeneration of neurons that expressed the injected PGC-1a than of other striatal cells, suggesting that it may be possible to restore the protein's protective effects.
"Our work provides specific, mechanistic evidence that energy deficits contribute to neuro-degeneration in HD and suggests that enhancing energy production in the brain may be neuroprotective. We are beginning to search for new compounds that could correct PGC-1a dysregulation and potentially reverse the disruption of energy metabolism in HD," says Krainc, who is an assistant professor of Neurology at Harvard Medical School.
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