An enzyme that naturally occurs in the brain, CHIP, helps destroy the mutated protein that is the most common cause of inherited Parkinson’s disease, researchers at UT Southwestern Medical Center have found.
Several mutations can affect this protein called leucine-rich repeat kinase 2 (LRRK2), some of which cause Parkinson’s. In its normal form, LRRK2 appears to have multiple sites where other molecules can attach themselves. The current theory is that the mutation the scientists studied leads to increased function of LRRK2, which in turn causes the formation of abnormal clumps of proteins inside brain nerve cells. The cells eventually die from these effects.
Using cultured human kidney cells, the investigators found that when CHIP bound to either the normal or mutant form of LRRK2, levels of LRRK2 in the cell decreased. This occurred because the cells increased the rate at which they destroyed LRRK2.
They also showed that LRRK2 forms a complex with overexpressed and endogenous CHIP and Hsp90. The data indicates that the destabilization of LRRK2 by CHIP is due to ubiquitination and proteasome-dependent degradation, the UT Southwestern team explains. Hsp90 can attenuate CHIP-mediated degradation, and this can be blocked by the Hsp90 inhibitor geldanamycin, they add.
“CHIP may be a useful therapeutic target for treatments to break down LRRK2 in people with Parkinson’s,” says Matthew Goldberg, Ph.D., assistant professor of neurology and psychiatry and senior author of the paper, which appears online in Public Library of Science. “Our next step is to identify cellular mechanisms that signal LRRK2 to be degraded by CHIP or by other mechanisms.” The paper in PloS is titled “Regulation of LRRK2 Stability by the E3 Ubiquitin Ligase CHIP.”
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Scientists Identify Mechanism through Which Cellular Aging Acts on a Protein Related to Parkinson’s (Mar. 21, 2008)
Researchers Discover Mechanism of Mutation Associated with Parkinson’s (June 19, 2007)