Treatment of Parkinson's Disease May Depend on Augmented Enzyme Activity

A naturally occurring brain enzyme has been identified that promotes the breakdown of the toxic protein clumps that characterize familial Parkinson's disease (PD) and some sporadic forms of the disease.

Dominantly inherited mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are the most common cause of familial PD and have also been identified in individuals with sporadic PD. Although the exact cellular function of LRRK2 remains unknown, most PD-linked mutations appear to be toxic to cells in culture via mechanisms that depend on the kinase activity of LRRK2 or on the formation of cytoplasmic inclusions.

Investigators at the University of Texas Southwestern Medical Center (Dallas, USA) reported in the June 17, 2009, online edition of the journal Public Library of Science (PLoS) One that they had identified an E3 ubiquitin ligase known as CHIP, which physically associated with LRRK2. CHIP regulated the cellular abundance of LRRK2 by forming a complex with LRRK2 and another protein; Hsp90. CHIP regulated LRRK2 through a process of ubiquitination and proteasome-dependent degradation.

"CHIP may be a useful therapeutic target for treatments to break down LRRK2 in people with Parkinson's," said senior author Dr. Matthew Goldberg, assistant professor of neurology and psychiatry at the University of Texas Southwestern Medical Center. "Our next step is to identify cellular mechanisms that signal LRRK2 to be degraded by CHIP or by other mechanisms. Because LRRK2 mutations are believed to cause Parkinsonism by increasing the activity of LRRK2, enhancing the normal mechanisms that target LRRK2 for degradation by CHIP may be therapeutically beneficial."
"There are currently enormous efforts to identify potential therapies based on inhibiting this mutated protein," said Dr. Goldberg. "Our paper is a major advance because we identify a protein that binds to the mutated protein and promotes its breakdown."

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University of Texas Southwestern Medical Center