by University of Southern California

Credit: Unsplash/CC0 Public Domain

A previously unidentified genetic mutation in a small protein provides significant protection against Parkinson's disease and offers a new direction for exploring potential treatments, according to a new USC Leonard Davis School of Gerontology study.

The variant, located in a mitochondrial microprotein dubbed SHLP2, was found to be highly protective against Parkinson's disease; individuals with this mutation are half as likely to develop the disease as those who do not carry it. The variant form of the protein is relatively rare and is found primarily in people of European descent.

The findings appear in the journal Molecular Psychiatry.

First discovered by Pinchas Cohen at the USC Leonard Davis School in 2016, SHLP2 is made within the cell's mitochondria. Previous research from the Cohen Lab established that SHLP2 is associated with protection from aging-related diseases including cancer and that levels of the microprotein change in patients with Parkinson's disease; they rise as the body attempts to counteract the pathology of Parkinson's disease but often fail to mount additional production as the disease progresses.

This latest finding builds upon the USC team's prior mitochondrial research and represents an advance at the intersection of longevity science, precision health, and microprotein discovery.

"This study advances our understanding of why people might get Parkinson's and how we might develop new therapies for this devastating disease," said Cohen, professor of gerontology, medicine and biological sciences and senior author of the study. "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."

For this study, first author Su-Jeong Kim, an adjunct research assistant professor of gerontology at the USC Leonard Davis School, led a series of experiments that leveraged the Lab-developed microprotein discovery pipeline that begins with a big data-driven analysis to identify variants involved in disease. Thousands of human study subjects from the Health & Retirement Study, Cardiovascular Health Study, and Framingham Heart Study were screened for the SHLP2 variant.

By comparing genetic variants in the mitochondrial DNA in patients with Parkinson's disease and in controls, researchers found a highly protective variant found in 1% of Europeans, that reduced risk of Parkinson's disease by twofold, to 50% of average.

Next, they demonstrated that this naturally occurring variant results in a change to the amino acid sequence and protein structure of SHLP2. The mutation—a single nucleotide polymorphism (SNP), or a change to a single letter of the protein's genetic code—is essentially a "gain-of-function" variant that is associated with higher expression of SHLP2 and also makes the microprotein more stable. According to their findings, the SHLP2 variant has high stability compared to the more common type and provides enhanced protection against mitochondrial dysfunction.

More information: Su-Jeong Kim et al, A naturally occurring variant of SHLP2 is a protective factor in Parkinson's disease, Molecular Psychiatry (2024). DOI: 10.1038/s41380-023-02344-0. www.nature.com/articles/s41380-023-02344-0

Journal information: Molecular Psychiatry 

Provided by University of Southern California