Newly identified SHMOOSE microprotein associated with Alzheimer’s disease risk

A newly discovered small protein mutation is associated with a significantly increased risk of Alzheimer’s disease (AD), according to a study conducted in humans and animal models led by researchers at Southern University. According to California (USC), Los Angeles. This discovery expands the number of known gene targets for AD and presents potential new therapeutics. A protein called SHMOOSE is a small microprotein encoded by a newly discovered gene within the energy-producing mitochondria of cells.

This study showed that intragenic mutations partially inactivate the SHMOOSE microprotein, which was associated with a 20-50% higher risk of AD across four different cohorts. They suggest that nearly a quarter of people of European descent carry a mutated version of the protein. They also note that both the high prevalence of his previously unidentified SHMOOSE mutation and the substantial risks associated with it distinguish this microprotein from other proteins implicated in AD. I paid attention. Aside from APOE4, the strongest known genetic risk factor for this disease, only a limited number of other genetic variants have been identified and these slightly increased risk by less than 10%. Additionally, SHMOOSE microproteins are roughly the same size as insulin peptides, which may facilitate administration, increasing therapeutic potential.

Pinchas Cohen, MD, professor of gerontology, medicine and biological sciences and senior author of the team’s study, said: It is published in molecular psychiatry“Administration of SHMOOSE analogues to individuals who carry the mutation and produce the mutant protein may prove beneficial in neurodegenerative and other diseases of aging,” Cohen and colleagues write. “Mitochondrial DNA mutations in Alzheimer’s disease reveal a unique microprotein called SHMOOSEIn it, they said, “Overall, SHMOOSE has great implications for the fields of neurobiology, Alzheimer’s disease, and microproteins.”

For decades, scientists have studied biology primarily in terms of a large set of 20,000 protein-coding genes. But new techniques have highlighted hundreds of thousands of potential genes that encode smaller microproteins. These are biologically active peptides encoded by small open reading frames (sORFs) of approximately 100 codons or less. As such, most microproteins have been missed in past genomics and proteomics studies, but as the authors noted, “…sophisticated techniques have now identified thousands of…mitochondrial-encoded microproteins. Microproteins are a potential, understudied part of Alzheimer’s disease.”

The USC Leonard Davis School of Gerontology claims to be the leader in research on microproteins, particularly those encoded within the mitochondrial genome. In 2003, Cohen and his colleagues were one of his three independent research teams. protein humanappears to have health-protective effects in Alzheimer’s disease, atherosclerosis, and diabetes. SHLPand microproteins called C word, An exercise mimetic peptide in clinical trials for obesity and fatty liver.

Brendan Miller, Ph.D., lead author of the newly reported study, used big data techniques to identify genetic variants in mitochondrial DNA associated with disease risk. After analysis revealed that gene mutations increased Alzheimer’s disease risk, brain atrophy, and energy metabolism, Miller and his colleagues discovered that the mutated gene (which he later named SHMOOSE.D47N) was mutated. We discovered that his SHMOOSE encodes his microprotein. The researchers say SHMOOSE is the first mitochondrial DNA-encoded microprotein detected using both antibodies and mass spectrometry. “SHMOOSE has been identified as the first biologically active mitochondrial-encoded microprotein detected by mass spectrometry, immunoblotting and ELISA,” they wrote. , we detected two unique SHMOOSE-derived peptide fragments in mitochondria, the first ever unique mass spectrometry-based detection of mitochondrial-encoded microproteins.”

Further work by the team on mutant and default forms of SHMOOSE showed that the microprotein appears to alter energy signaling and metabolism in the central nervous system. That level of was correlated with a biomarker of Alzheimer’s disease. “…human cerebrospinal fluid (CSF) SHMOOSE levels correlated with age, CSF tau, and brain white mass,” they continued. Various cell culture and animal studies have shown that SHMOOSE partially alters brain energy metabolism by inhibiting the mitochondrial inner membrane, an important part of mitochondria. “…SHMOOSE acted on the brain after intracerebroventricular administration, differentiated mitochondrial gene expression in multiple models, localized to mitochondria, bound to the mitochondrial inner membrane protein Mitofilin, and enhanced mitochondrial oxygen consumption.”

According to Miller, the findings highlight the importance of the relatively new field of microproteins. “The microprotein field is still new,” he says Miller. “The number of functioning microprotein genes is not yet known. The cost of studying potential microproteins one by one from a list of thousands is too expensive and inefficient. A colleague and I detect SHMOOSE.” The approach we used to do this demonstrates the power of integrating large genetic data with molecular and biochemical techniques to discover functional small proteins.”

The results also demonstrate that mitochondrial DNA variants may be associated with several neurobiological phenotypes and that mitochondrial DNA variants can be mapped to sORFs that encode biologically functional microproteins. I’m here. “We identified SHMOOSE as the first biologically active mitochondrial-encoded microprotein detected by mass spectrometry, immunoblot and ELISA,” they said. Correlations between SHMOOSE, CSF AD-related biomarkers (such as tau), and CSF levels in brain white matter also suggest that SHMOOSE has potential as a biomarker, commenting the authors. there is “Finally, SHMOOSE is another microprotein in increasing numbers that alters mitochondrial biology.”