Researchers from the USC Leonard Davis School of Gerontology have unearthed a previously unidentified genetic mutation that could help pioneer new Parkinson’s disease treatments.
The discovery of this variant in a mitochondrial microprotein called SHLP2 not only shields individuals from the disease but also opens up promising avenues for exploring potential Parkinson’s disease treatments.
The study, led by Professor Pinchas Cohen and his team, sheds light on the profound protective effects of the SHLP2 variant.
Individuals carrying this genetic mutation exhibit a remarkable 50% reduced likelihood of developing Parkinson’s disease compared to those without it.
Intriguingly, this variant is relatively uncommon and is primarily found amongst people of European descent.
This breakthrough builds upon Cohen’s prior research on SHLP2, initially discovered in 2016, which indicated its association with safeguarding against aging-related diseases such as cancer.
The latest findings accentuate its role in Parkinson’s disease, where levels of SHLP2 fluctuate in an attempt to counteract the disease’s progression but often fail to maintain sufficient production.
“This study advances our understanding of why people might get Parkinson’s and how we might develop new therapies for this devastating disease,” stated Cohen.
“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 ageing.”
How SHLP2 protects against Parkinson’s disease
The research, spearheaded by first author Su-Jeong Kim, employed an extensive series of experiments leveraging a microprotein discovery pipeline developed by the Cohen Lab.
Screening thousands of individuals from various studies, including the Health & Retirement Study and the Framingham Heart Study, revealed the protective SHLP2 variant present in approximately 1% of Europeans, cutting the risk of Parkinson’s disease by half.
Further analysis uncovered that this genetic variant induces a change in the structure and amino acid sequence of SHLP2. Essentially a ‘gain-of-function’ mutation, it boosts the expression and stability of the microprotein.
Impressively, the mutant form of SHLP2 was found to bind more effectively to an essential mitochondrial enzyme, mitochondrial complex 1, crucial for cell function.
Innovating novel treatments
The study demonstrated that this heightened stability of SHLP2 preserves mitochondrial complex 1’s activity, mitigating mitochondrial dysfunction – a hallmark of Parkinson’s disease.
The team corroborated their findings through experiments conducted on human tissue samples and mouse models, revealing the tangible benefits of the SHLP2 variant in reducing the disease’s impact.
“These findings may guide the development of therapies and provide a roadmap for understanding other mutations found in mitochondrial microproteins,” noted Kim, underscoring the potential implications for future therapeutic interventions.
The USC team’s groundbreaking research not only unravels the protective mechanisms of a specific gene variant but also illuminates potential molecular pathways for mitigating Parkinson’s disease.
This discovery marks a significant leap in advancing precision health and holds promise for innovative treatments targeting age-related neurological conditions.
