Newly discovered genetic mutation protects against Parkinson’s disease and offers hope for new therapies

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 study from the USC Leonard Davis School of Gerontology.

The variant, located in a mitochondrial microprotein called SHLP2, was found to be highly protective against Parkinson’s disease; individuals carrying 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 results appear in the journal Molecular Psychiatry.

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

This latest discovery builds on the USC team’s previous mitochondria research and represents an advancement at the intersection of longevity science, precision health, and microprotein discovery.

“This study advances our understanding of why people might get Parkinson’s disease and how we might develop new treatments for this devastating disease,” said Cohen, professor of gerontology, medicine and biological sciences and senior author. of the study. “Furthermore, as most research focuses on genes encoding well-established proteins in the nucleus, it highlights the relevance of exploring mitochondria-derived microproteins as a novel approach to the prevention and treatment of heart-related diseases. aging.”

For this study, first author Su-Jeong Kim, 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 an analysis based on big data to identify variants involved in disease. Thousands of human study subjects from the Health & Retirement Study, the Cardiovascular Health Study, and the Framingham Heart Study were screened for the SHLP2 variant.

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

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

The research team was able to use targeted mass spectrometry techniques to identify the presence of the tiny peptide in neurons and discovered that SHLP2 binds specifically to an enzyme in mitochondria called mitochondrial complex 1. This enzyme is essential for life and its decline in function has been linked not only to Parkinson’s disease, but also to strokes and heart attacks.

The increased stability of the SHLP2 variant means that the microprotein binds to mitochondrial complex 1 more stably, prevents the decline of enzyme activity and thus reduces mitochondrial dysfunction. The benefits of the mutant form of SHLP2 were observed both in in vitro experiments on human tissue samples as well as in mouse models of Parkinson’s disease, according to the study.

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

Co-authors included Brendan Miller, Nicolas G. Hartel, Ricardo Ramirez II, Regina Gonzalez Braniff, Naphada Leelaprachakul, Amy Huang, Yuzhu Wang, Thalida Em Arpawong, Eileen M. Crimmins, Kelvin Yen, Giselle M. Petzinger, Michael W. Jakowec. , and Nicholas A. Graham of USC; Penglong Wang and Chunyu Liu of the National Heart, Lung, and Blood Institute, National Institutes of Health; and Xianbang Sun and Daniel Levy of Boston University.