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Researchers Identify Key Proteins Involved in Neurodegeneration of Huntington’s Disease
The discovery was reported in the July 11 online issue of Science Translational Medicine.
In HD, an inherited mutation in the huntingtin (htt) gene causes misfolded htt proteins to accumulate in certain central nervous system cells, leading to progressive deterioration of involuntary movement control, cognitive decline, and psychological problems.
The research by Dr. La Spada and colleagues focused on a protein called PGC-1alpha, which helps regulate the creation and operation of mitochondria, the tiny organelles that generate the fuel required for cells to function. Previous studies by Dr. La Spada and others had found that a mutant form of the htt gene interfered with normal levels and functioning of PGC-1alpha. The new findings confirmed that discovery. In addition, the researchers found that elevated levels of PGC-1alpha in a mouse model of HD virtually eliminated the problematic misfolded proteins.
The investigators also found that PGC-1alpha drives the recycling of mitochondria through another protein called TFEB. Even without PCG-1alpha induction, TFEB can prevent the aggregation of misfolded htt proteins and associated neurotoxicity.
Thus, PGC-1alpha and TFEB provide two new therapeutic targets for Huntington’s disease, according to Dr. La Spada.
“If you can induce the bioenergetics and protein quality control pathways of nervous system cells to function properly, by activating the PGC-1alpha pathway and promoting greater TFEB function, you stand a good chance of maintaining neural function for an extended period of time,” he said. “If we could achieve the level of increased function necessary to eliminate misfolded proteins, we might nip the disease process in the bud.”
Read the news release from the University of California.