The down-regulation of a key gene in the striatum, a region of the brain attacked in Huntington disease (HD), may be a defensive measure taken by striatal cells to try to avoid ultimate destruction in the HD process. The down-regulated gene (CalDAG-GEFI) is normally highly enriched in the striatal cells that are targeted in HD. An MIT research team, together with collaborators, showed that CalDAG-GEFI gene expression is dramatically down-regulated in the brains of individuals with HD, as well as in mouse models of the disease. By following mutant mice for up to nine months, the researchers further showed that this reduction occurred gradually, in parallel with the progression of the disease. These progressive changes suggested that CalDAG-GEFI is likely to play some role in the disease process. The researchers wanted to determine whether the suppression of this gene is part of the death process, or whether it represents part of the brain’s protective response. They found that the latter explanation appears to be true--when the researchers artificially blocked the expression of CalDAG-GEFI, the striatal neurons were protected from damage induced by the mutant huntingtin (Htt) protein. “So the enriched expression of CalDAG-GEFI in the striatum may explain, in part, why striatal neurons are particularly vulnerable to the expression of mutant Htt,” explained first author Dr. Jill Crittenden of the MIT McGovern Institute for Brain Research. “Switching off of the CalDAG-GEFI gene may represent the neuron’s attempt, ultimately unsuccessful, to save itself.” The researchers hope that by understanding the molecular pathway by which neurons are killed, their findings may suggest new strategies for the development of treatments that could slow or even prevent the progression of HD.
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