A mutation in a recently discovered small protein is linked to a significantly increased risk of Alzheimer’s (AD), according to the results of a study, conducted in humans and in animal models, and led by researchers from the University of Southern California ( USC), Los Angeles. The findings expand the number of known gene targets for AD and present a potential new avenue for treatment. The protein, called SHMOOSE, is a tiny microprotein encoded by a newly discovered gene within the cell’s energy-producing mitochondria.
The study showed that a mutation within the gene partially inactivates the SHMOOSE microprotein and that this was associated with a 20-50% higher risk of AD in four different cohorts. They suggest that nearly a quarter of people of European descent have the mutated version of the protein. They also noted that both the high prevalence of the previously unidentified SHMOOSE mutation and the substantial risk associated with it differentiate this microprotein from other proteins involved in AD. Aside from APOE4, the most potent known genetic risk factor for the disease, only a limited number of other genetic mutations were identified and these only slightly increased the risk by less than 10%. furthermore, the SHMOOSE microprotein is about the size of the insulin peptide, so it could potentially be easily administered, which increases its therapeutic potential.
“This discovery opens exciting new directions for the development of precision medicine-based therapies for Alzheimer’s disease, focusing on SHMOOSE as a target area,” said Pinchas Cohen, MD, professor of gerontology, medicine and biological sciences and senior author of the team study, which is published in Molecular Psychiatry. “The administration of SHMOOSE analogues in individuals carrying the mutation and producing the mutant protein may prove beneficial in neurodegenerative and other diseases of aging.” Cohen and colleagues reported their findings in a paper titled “Mitochondrial DNA variation in Alzheimer’s reveals a unique microprotein called SHMOOSE,” in which they concluded: “Overall, SHMOOSE has broad implications for the fields of neurobiology, Alzheimer’s and microproteins. “
For decades, scientists have studied biology primarily by looking at a collection of 20,000 large protein-coding genes. However, the new technology has revealed hundreds of thousands of potential genes that code for smaller microproteins. These are biologically active peptides, encoded by small open reading frames (sORFs), of approximately 100 codons or less. Thus, while most microproteins have not been detected by previous genomic and proteomic studies, as the authors have noted, “… now thousands have been identified due to refined techniques … The encoded microproteins in mitochondria they are a potential part of AD that has not been thoroughly studied. “
The USC Leonard Davis School of Gerontology claims to be a leader in the study of microproteins, particularly those encoded within the mitochondrial genome. In 2003, Cohen and his colleagues were one of three research groups to independently discover the humanin protein, which appears to have protective health effects in Alzheimer’s, atherosclerosis and diabetes. In recent years, the Cohen lab has discovered several other mitochondrial microproteins, including small human-like peptides, or SHLPs, and a microprotein called MOTS-c, an exercise mimetic peptide that has entered clinical trials for obesity. and fatty liver.
Brendan Miller, PhD, first author of the study just reported, used big data techniques to identify genetic variations in mitochondrial DNA associated with disease risk. After analyzes revealed that a genetic mutation increased the risk of Alzheimer’s, brain atrophy, and energy metabolism, Miller and his colleagues found that the mutated gene (which they later designated SHMOOSE.D47N) encoded a mutated SHMOOSE microprotein. . The researchers said SHMOOSE is the first microprotein encoded in mitochondrial DNA to be detected using both antibodies and mass spectrometry. “We identified SHMOOSE as the first biologically active mitochondrial encoded microprotein detected by mass spectrometry, immunoblot and ELISA,” they wrote. “… we detected two SHMOOSE-derived peptide fragments in mitochondria using mass spectrometry, the first unique mass spectrometry-based detection of a mitochondrial encoded microprotein to date.”
The team’s further study of mutated and predefined forms of SHMOOSE indicated that the microprotein appears to modify energy signaling and metabolism in the central nervous system. It was found in the mitochondria of neurons, and its levels in cerebrospinal fluid correlated with Alzheimer’s disease biomarkers. “… cerebrospinal fluid (CSF) SHMOOSE levels in humans correlated with age, cerebrospinal fluid tau, and brain white matter volume,” they continued. A variety of cell cultures and animal experiments have shown that SHMOOSE alters energy metabolism in the brain in part by inhibiting a crucial part of the mitochondria, the inner mitochondrial membrane. “… SHMOOSE acted on the brain following intracerebroventricular administration, differentiated mitochondrial gene expression in multiple patterns, located in the mitochondria, bound the inner mitochondrial membrane protein mitophilin and increased mitochondrial oxygen consumption.”
Miller said the findings highlight the importance of the relatively new field of microproteins. “The field of microproteins is still so new,” Miller said. “We still don’t know how many microprotein genes are functional and the cost of studying a potential microprotein one by one from a list of thousands is simply too expensive and inefficient. The approach my colleagues and I used to detect SHMOOSE shows the power of integrating large genetic data with molecular and biochemical techniques to discover functional microproteins.
The results also demonstrated that mitochondrial DNA variants can associate with different neurobiological phenotypes and that mitochondrial DNA variants can be mapped to sORFs that encode biologically functional microproteins. “We identified SHMOOSE as the first biologically active mitochondrial encoded microprotein detected by mass spectrometry, immunoblot and ELISA,” they noted. The correlation between SHMOOSE levels in CSF, AD-related biomarkers (e.g., tau), and brain white matter also suggests that SHMOOSE has potential as a biomarker, the authors commented. “Finally, SHMOOSE is another microprotein of an increasing number that modifies mitochondrial biology.”