A newly discovered genetic mutation in a protein called SHLP2 offers strong protection against Parkinson’s disease, according to a study from USC Leonard Davis School of Gerontology. This variant in the mitochondrial microprotein SHLP2 significantly reduces the risk of developing Parkinson’s, making carriers half as likely to get the disease. The mutation is rare and mainly found in people of European descent.
The study, published on January 3, 2024, in Molecular Psychiatry, opens up new possibilities for exploring treatments for Parkinson’s.
Discovered in 2016 by Pinchas Cohen at USC Leonard Davis School, SHLP2 is produced in cell mitochondria. Previous research from Cohen Lab showed SHLP2 protects against aging-related diseases, including cancer. In Parkinson’s, SHLP2 levels rise to counteract the disease but often decrease with progression.
The recent discovery expands on USC’s mitochondrial research, advancing longevity science, precision health, and microprotein understanding.
Cohen, professor of gerontology, medicine, and biological sciences and senior author of the study, said, “This study advances our understanding of why people might get Parkinson’s and how we might develop new therapies for this devastating disease. 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.”
In this study, led by Su-Jeong Kim, a USC Leonard Davis School researcher, experiments used a Lab-developed microprotein discovery method. By analyzing big data, they identified a protective SHLP2 variant in 1% of Europeans, reducing Parkinson’s risk by half. This variant, resulting from a single genetic code change, enhances SHLP2 stability and expression, providing extra protection against mitochondrial dysfunction.
The research, involving thousands from health studies, sheds light on a naturally occurring variant’s impact on Parkinson’s risk and microprotein function.
The research team used mass spectrometry to find SHLP2 in neurons, discovering it binds to a crucial enzyme in mitochondria, mitochondrial complex 1. This enzyme is vital for life and is linked to conditions like Parkinson’s, strokes, and heart attacks when its function declines.
The stable SHLP2 variant binds more effectively to mitochondrial complex 1, preventing enzyme activity decline and reducing mitochondrial dysfunction. The positive effects of the mutated SHLP2 were observed in both human tissue samples and mouse models of Parkinson’s disease in lab experiments.
Kim said, “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. These findings may guide the development of therapies and provide a roadmap for understanding other mutations found in mitochondrial microproteins.”
In conclusion, the recently found genetic mutation, SHLP2 variant, offers protection against Parkinson’s disease. This discovery holds promise for developing new therapies to tackle this condition.
Journal reference:
Kim, SJ., Miller, B., Hartel, N.G. et al. A naturally occurring variant of SHLP2 is a protective factor in Parkinson’s disease. Molecular Psychiatry. DOI: 10.1038/s41380-023-02344-0.
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