• 18 Jun, 2024

A previously undiscovered genetic mutation in a small protein offers significant protection against Parkinson's disease and opens a new direction for research into possible treatments, according to a new study from the USC Leonard Davis School of Gerontology.

A variant located in a mitochondrial microprotein called SHLP2 is very effective in preventing Parkinson's disease. People with this mutation are half as likely to develop the disease as those without it. This variant form of the protein is relatively rare and occurs mainly in people of European descent.

The results of this study were published in the journal Molecular Psychiatry. SHLP2, first discovered in 2016 by Pinchas Cohen of the USC Leonard Davis School, is produced in the mitochondria of cells. Previous research from Cohen's lab has shown that SHLP2 is associated with protection against diseases of aging, including cancer, and that levels of the microprotein are altered in patients with Parkinson's disease.

They multiply as the body tries to fight the pathology of Parkinson's disease, but often fail to generate additional production as the disease progresses. This latest discovery builds on previous research by the USC mitochondrial team and represents a breakthrough at the intersection of longevity science, precision health, and microprotein discovery.

"This study helps us understand why people develop Parkinson's disease and how we can develop new treatments for this devastating disease," said Cohen, lead author of the study and professor of gerontology, medicine, and biology. "Since most research is done on genes that encode proteins in the nucleus, this highlights the relevance of studying mitochondria-derived microproteins as a new way to prevent and treat diseases of aging."

For this study, first author Sujeong Kim, an assistant professor of gerontology at the USC Leonard Davis School, performed a series of experiments using a microprotein discovery pipeline developed in the lab and performed analyses on pig data to identify spliced ​​variants. With this one. to illness.

Thousands of people who participated in the Health and Retirement Study, the Cardiovascular Health Study, and the Framingham Heart Study were tested for SHLP2 variants. By comparing genetic variants in the mitochondrial DNA of Parkinson's patients and controls, the researchers discovered a highly protective variant found in 1% of Europeans that doubled the risk of developing Parkinson's disease by an average of 50%.

They then showed that this natural variant causes changes in the amino acid sequence and structure of the SHLP2 protein. Mutations (single nucleotide polymorphisms (SNPs) or single-letter changes in the genetic code of the protein) are gain-of-function variants associated with higher expression of SHLP2 and also make the microprotein more stable.

The results show that SHLP2 variants are more stable compared to the regular form and provide increased protection against mitochondrial dysfunction. Using targeted mass spectrometry techniques, the team was able to detect the presence of small peptides in neurons and discovered that SHLP2 specifically binds to an enzyme called mitochondrial complex 1 in the mitochondria.

This enzyme is essential for life and its function is reduced. It is associated not only with Parkinson's disease but also with stroke and heart attack.

The increased stability of SHLP2 variants suggests that the microprotein binds more stably to mitochondrial complex 1, preventing a decrease in enzyme activity and thus reducing mitochondrial dysfunction. Studies have observed the benefits of mutant forms of SHLP2 in vitro experiments using human tissue samples and mouse models of Parkinson's disease.

"Our data highlight the biological effects of specific genetic mutations and the potential molecular mechanisms by which these mutations may reduce the risk of Parkinson's disease," Kim said. "These findings may guide the development of treatments and provide a roadmap for understanding other mitochondrial microprotein mutations."

Co-authors include Brendan Miller, Nicholas J., Yuzhu Wang, Talida Em Arpawong, Eileen M. Crimmins, Calvin Yen, Giselle M. Hartel, Regina Gonzalez Braniff, Ricardo Ramirez II, Regina Gonzalez Braniff Petzinger, Michael W. Jacobek, and Nicholas A. Graham at USC; Penglong Wang and Chunyu Liu of the National Heart, Lung, and Blood Institute, National Institutes of Health; and Xiangbang Sun and Daniel Levy of Boston University.