Rare protein mutation shields against Parkinson’s disease, study finds

A genetic mutation in a microprotein could safeguard individuals from developing Parkinson's disease, according to a new research study conducted by the USC Leonard Davis School of Gerontology. Parkinson's disease, a crippling neurological disorder, affects millions of people globally. The mutation is found in a mitochondrial microprotein, SHLP2, which was first identified by USC professor Pinchas Cohen in 2016.

The research, published in the journal on January 3, 2024, indicated that those with the mutation have a 50% lower risk of contracting Parkinson's disease compared to those without it. The mutation primarily found in individuals of European descent is present only in 1%. This mutation modifies both the structure and function of the microprotein, making it more stable and successful in averting mitochondrial dysfunction, a crucial factor in the development of Parkinson's disease.

Mitochondria serve as a cell’s powerhouses, producing energy and regulating cellular functions. These include SHLP2, a mitochondrial microprotein that plays an essential role in maintaining their health and function. Past research indicates that SHLP2 safeguards against age-related diseases like cancer, and its levels fluctuate in patients with Parkinson's disease.

USC professor Pinchas Cohen said, "These findings shed light on the molecular mechanisms of Parkinson's disease and pave the way for possible treatments. It also emphasizes the potential use of mitochondrial microproteins as innovative targets for preventing and treating aging disorders."

The study led by Su Jeong Kim, an adjunct research assistant professor of gerontology at the USC Leonard Davis School, discovered the SHLP2 mutation by conducting a large-scale genetic analysis and using data from three different cohorts: the Health & Retirement Study, the Cardiovascular Health Study, and the Framingham Heart Study.

She then conducted a series of studies to verify the mutation's protective effect on mitochondrial function and Parkinson's disease risk. Kim found that the mutation causes a higher expression of SHLP2 and a more stable structure of the microprotein. She also discovered that SHLP2 attaches to a key enzyme in the mitochondria, mitochondrial complex 1, whose activity lessens in Parkinson's disease and safeguards mitochondrial function by binding more securely to this enzyme.

The study is part of continuing research from the USC team on mitochondrial microproteins and their impact on aging and disease. The researchers' findings could pave the way for new therapies for Parkinson's disease and other age-related disorders. The mutant form of SHLP2 showed promising effects in both human tissue samples and mouse models of Parkinson's disease. These findings offer a blueprint for understanding other mutations found in mitochondrial microproteins and steering the development of treatments.