A previously unrecognized genetic mutation in a small protein confers significant protection against Parkinson’s disease and offers a new direction for exploring potential treatments, according to a new Gerontology study by 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. People with this mutation are half as likely to develop the disease as those without it. The protein variant is relatively rare and is found mainly in people of European descent.
The findings appear Jan. 3, 2024, in the journal Molecular Psychiatry.
First discovered by Pinchas Cohen at the USC Leonard Davis School in 2016, SHLP2 is produced in the cell’s mitochondria. Previous research from the Cohen Lab has shown that SHLP2 is associated with protection against aging-related diseases, including cancer, and that levels of the microprotein are altered in patients with Parkinson’s disease. They rise as the body tries to neutralize the pathology of Parkinson’s disease, but often fail to increase production as the disease progresses.
This latest finding builds on the USC team’s previous 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 may develop Parkinson’s 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. “Also, because most research is done on established protein-coding genes in the nucleus, it highlights the importance of exploring mitochondria-derived microproteins as a new approach to preventing and treating diseases of aging.”
For this study, first author Su-Jeong Kim, assistant research assistant professor of gerontology at the USC Leonard Davis School, led a series of experiments that leveraged the lab’s microprotein discovery pipeline that begins with a big data-driven analysis of identifying variants involved in the disease. Thousands of 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 in mitochondrial DNA in Parkinson’s disease patients and controls, researchers found a highly protective variant found in 1% of Europeans that reduced the risk of Parkinson’s disease by half, to 50% of the average.
They then showed that this natural variation results in a change in the amino acid sequence and protein structure of SHLP2. The mutation — a single nucleotide polymorphism (SNP), or change in 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.
The research team was able to use targeted mass spectrometry techniques to identify the presence of the tiny peptide in neurons and found that SHLP2 binds specifically to an enzyme in the mitochondria called mitochondrial complex 1. This enzyme is essential for life and decreases in its 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, preventing a drop in enzyme activity and thus reducing mitochondrial dysfunction. The benefits of the mutant form of SHLP2 were seen in both in vitro experiments in human tissue samples and in mouse models of Parkinson’s disease, according to the study.
“Our data highlight the biological effects of a particular gene variant and the possible 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 road map for understanding other mutations found in mitochondrial microproteins.”
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. 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.
This work was supported by Department of Defense grant W81XWH2110625 to Kim and by NIH grants P01AG034906, R01AG068405, and P30AG068345 to Cohen. Pinchas Cohen is a consultant to CohBar Inc.