The variant, located in a mitochondrial microprotein dubbed SHLP2, was found to be highly protective against Parkinson’s disease; individuals with this mutation are half as likely to develop the disease as those who do not carry it. The variant form of the protein is relatively rare and is found primarily in people of European descent.

The findings appear on January 3, 2024, in the journal Molecular Psychiatry.

First discovered by Pinchas Cohen at the USC Leonard Davis School in 2016, SHLP2 is made within the cell’s mitochondria. Previous research from the Cohen Lab established that SHLP2 is associated with protection from aging-related diseases including cancer and that levels of the microprotein change in patients with Parkinson’s disease; they rise as the body attempts to counteract the pathology of Parkinson’s disease but often fail to mount additional production as the disease progresses.

This latest finding builds upon the USC team’s prior 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 might get Parkinson’s and how we might develop new therapies 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 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.”

For this study, first author Su-Jeong Kim, an adjunct research assistant professor of gerontology at the USC Leonard Davis School, led a series of experiments that leveraged the Lab-developed microprotein discovery pipeline that begins with a big data-driven analysis to identify variants involved in disease. Thousands of human study subjects from the Health & Retirement Study, Cardiovascular Health Study, and Framingham Heart Study were screened for the SHLP2 variant. By comparing genetic variants in the mitochondrial DNA in patients with Parkinson’s disease and in controls, researchers found a highly protective variant found in 1% of Europeans, that reduced risk of Parkinson’s disease by twofold, to 50% of average.

Next, they demonstrated that this naturally occurring variant results in a change to the amino acid sequence and protein structure of SHLP2. The mutation — a single nucleotide polymorphism (SNP), or a change to 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 tiny peptide’s presence in neurons and found that SHLP2 specifically binds to an enzyme in mitochondria called mitochondrial complex 1. This enzyme is essential for life, and declines in its function have 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, prevents the decline of the enzyme’s activity, and thus reduces mitochondrial dysfunction. The benefits of the mutant form of SHLP2 were observed in both in vitro experiments in human tissue samples as well as in mouse models of Parkinson’s disease, according to the study.

“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 Kim. “These findings may guide the development of therapies and provide a roadmap for understanding other mutations found in mitochondrial microproteins.”

Coauthors 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. Jakowec, and 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 of CohBar Inc.

In the study, published in the November issue of the journal Applied Spectroscopy, researchers from DRI and the UC Davis Tahoe Environmental Research Center teamed up with the nonprofit Clean Up the Lake to take a close look at the litter. First, scientists broke it down into categories based on use (such as food containers and water bottles), followed by the chemical composition of the plastic. The knowledge gained can help scientists better understand the source of large pieces of litter in the lake, as well as whether they’re a significant source of microplastics as larger pieces break down and degrade. Previous research found that the waters of Lake Tahoe contain high levels of microplastics, defined as plastics smaller than a pencil eraser.

“There’s very little work on submerged plastic litter in lakes,” said Monica Arienzo, Ph.D., associate research professor of hydrology at DRI and one of the study’s lead authors. “And I think that’s a real issue, because when we think about how plastics may be moving in freshwater systems, there’s a good chance that they’ll end up in a lake.”

To collect the litter, research divers swam transects along the lakebed near Lake Tahoe Nevada State Park and Zephyr Cove, covering 9.3 kilometers. They found an average of 83 pieces of plastic litter per kilometer, with the lakebed near Hidden Beach and South Sand Harbor showing significantly more (140 items/km and 124 items/km, respectively). No stretches of the lakebed surveyed were free of plastic litter.

The most common plastic litter categories were food containers, bottles, plastic bags, and toys, along with many items that couldn’t be categorized.

“There’s a lot of education we can do, as well as continuing to work on reducing the use of those plastics,” Arienzo says. “Because we have to start thinking about turning that plastic pipe off.”

Arienzo and co-author Julia Davidson, then an undergraduate student working in Arienzo’s lab, also identified the types of plastic that made up 516 of the litter samples. Using an instrument that uses infrared light to fingerprint and identify the material, they found that the six most common plastics were polyvinyl chloride (PVC), polystyrene, polyester/polyethylene terephthalate, polyethylene, polypropylene, and polyamide. Collecting this information can contribute to Arienzo’s ongoing microplastics research in the region, helping to identify the sources of the small plastic fragments.

“When we study microplastics, we only have the chemical information, or the plastic type,” Davidson says. “We don’t know where it came from — a plastic bag, toy, or otherwise — because it’s just a tiny piece of plastic. But now we can use this litter data to point to the dominant types of plastics and compare them to microplastic data.”

The study can help inform efforts by Tahoe-area communities to address plastic litter, such as South Lake Tahoe’s 2022 ban on single-use plastic bottles and Truckee’s ban on single-use food containers. The research also highlights ways that scientists can work with nonprofits to collect data that can address local environmental concerns.

“I think one of the things that’s really cool about this project is the collaboration between DRI, Clean Up the Lake, and UC Davis at Tahoe,” Arienzo says. “It demonstrates the power of bringing together a nonprofit that really wants to clean up Tahoe, while collecting data in the process that can help answer scientific questions.”