Scientists have identified a genetic mutation in a gene called SHLP2, which encodes for a microprotein in mitochondria, and can reduce a carrier's likelihood of developing Parkinson's disease by 50 percent, compared to those not carrying it. This finding could offer new insights into treating the neurodegenerative disease as well. The research has been reported in Molecular Psychiatry.
This genetic mutation or variant was identified primarily in people of European descent. It is located in mitochondrial DNA, a special type of DNA that is found in mitochondria, as opposed to genomic DNA that is in the nucleus. Mitochondrial DNA is used to make special mitochondrial proteins. SHLP2 is one of those mitochondrial proteins, and has been linked to age-related diseases in previous studies by this research group. SHLP2 expression seems to increase in Parkinson's patients as their bodies counteract the disease.
This work has emphasized the importance of microproteins that derive from mitochondrial DNA, noted senior study author Pinchas Cohen, a professor at the University of Southern California's (USC) Leonard Davis School of Gerontology.
These microproteins could pave the way to new treatments for diseases that are linked to aging, added Cohen.
In this work, the investigators screened the DNA of thousands of people who have volunteered for the Health & Retirement Study, Cardiovascular Health Study, and Framingham Heart Study. They determined that the SHLP2 variant was highly protective, and made Parkinson's disease about 50 percent less likely in those with the variant. This mutation was found in about 1 percent of people of European descent.
The mutation, which occurs in only a single base pair, alters the SHLP2 protein by one amino acid. It is what is referred to as a gain-of-function mutation, and generates a SHLP2 protein with greater stability. This mutated protein is much more stable than the common version, and helps prevent dysfunction in mitochondria.
The researchers also found that SHLP2 can bind to an enzyme called mitochondrial complex 1, an enzyme whose function is known to decline with age. The mutant SHLP2, with its increased stability, can stop the enzyme's activity from declining, promoting healthy mitochondrial function.
These findings were confirmed in human tissue samples in addition to mouse models of Parkinson's.
"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," said first study author Su-Jeong Kim, an adjunct research assistant professor at USC. "These findings may guide the development of therapies and provide a roadmap for understanding other mutations found in mitochondrial microproteins."
Sources: University of Southern California, Molecular Psychiatry