The hands of a man with Parkinson's disease tremble. Strongly trembling hands of an older man
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Researchers at the University of Southern California (USC) reported this week they have newly identified a genetic mutation in a small protein that provides significant protection against the development of Parkinson’s disease. This new finding, reported in the journal Molecular Psychiatry, makes this beneficial variant an important target for developing new treatments against the disease.

The variant, located on the mitochondrial protein called SHLP2, was found to be highly protective against Parkinson’s disease. Those people who harbor the mutation had half the risk of developing the disease compared with those who don’t have it. The investigators further noted that the variant form of the protein is rare and found primarily in people of European descent.

“This study advances our understanding of why people might get Parkinson’s and how we might develop new therapies for this devastating disease,” said senior author Pinchas Cohen, professor of gerontology, medicine and biological sciences at the USC Leonard Davis School of Gerontology. “Also, because most research is done on well-established protein-coding genes in the nucleus, it underscores the relevance of exploring mitochondrial-derived microproteins as a new approach to the prevention and treatment of diseases of aging.”

Cohen first discovered SHLP2 in 2016 and other research conducted in his lab has found that the microprotein is associated with protection from aging-related diseases and cancer. His lab also discovered that in patients with Parkinson’s, levels of the SHLP2 change—rising as the body tries to fight against the disease’s pathology, then lessening production as the disease progresses.

For this research, Su-Jeong Kim an adjunct research assistant professor of gerontology at the USC Leonard Davis School and the study’s first author used big data analysis to identify variants associated with Parkinson’s by screening the data from the Health & Retirement Study, Cardiovascular Health Study, and Framingham Heart Study to identify those people who possessed the SHLP2 variant. This variant, found in 1% of all patients of European descent, reduced the risk of Parkinson’s by two-fold, or 50%.

The team then demonstrated that the mutation is a single-nucleotide polymorphism, or SNP, and acts as a gain of function variant that is associated with higher SHLP2 expression, which also makes the protein more stable. This added stability is exhibited in SHLP2’s binding to the mitochondrial complex 1, which prevents the decline of the enzyme’s activity, which, in turn, reduces mitochondrial dysfunction. The investigators demonstrated this effect in both human tissue samples and Parkinson’s disease mouse models.

“Our data highlights the biological effects of a particular gene variant and the potential molecular mechanisms by which this mutation may reduce the risk for Parkinson’s disease,” said Kim. “These findings may guide the development of therapies and provide a roadmap for understanding other mutations found in mitochondrial microproteins.”

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