A mutation in a newly discovered small protein is linked to a significantly increased risk of Alzheimer’s disease, expanding known genetic targets for the disease and presenting a potential new avenue for treatment, according to a new study from USC.
The protein, called SHMOOSE, is a tiny “microprotein” encoded by a recently discovered gene in the cell’s energy-producing mitochondria. A mutation within this gene partially inactivates the SHMOOSE microprotein and is associated with a 20-50% increased risk of Alzheimer’s disease in four different cohorts. Nearly a quarter of people of European ancestry have the mutated version of the protein, according to the researchers.
The research appears Wednesday, September 21 in the journal Molecular psychiatry.
The researchers say the substantial risk and high prevalence of this previously unidentified mutation differentiates it from other proteins implicated in Alzheimer’s disease. Apart from APOE4 -; the most potent known genetic risk factor for the disease -; only a limited number of other genetic mutations have been identified and these only slightly increase the risk by less than 10%. Additionally, because the microprotein is approximately the size of the insulin peptide, it can be easily administered, increasing 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. Administration of SHMOOSE analogs to people who carry the mutation and produce the mutant protein may prove beneficial in neurodegenerative and other diseases of aging.
Pinchas Cohen, professor of gerontology, medicine and biological sciences and lead author of the study
Brendan Miller, 22, a PhD in neuroscience and first author of the study, 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 disease, brain atrophy and energy metabolism, Miller and his colleagues discovered that the mutated gene encoded the microprotein SHMOOSE and began to study its effects. mutated and default forms. The researchers said SHMOOSE is the first microprotein encoded by mitochondrial DNA to be detected using both antibodies and mass spectrometry.
The microprotein appears to alter 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 biomarkers of Alzheimer’s disease. A variety of cell culture and animal experiments have shown that SHMOOSE alters energy metabolism in the brain in part by inhabiting a crucial part of mitochondria, the inner mitochondrial membrane.
An emerging field of study
Miller said the findings underscore the importance of the relatively new field of microproteins. For decades, scientists have studied biology primarily by looking at a set of 20,000 large protein-coding genes. However, new technology has revealed hundreds of thousands of potential genes that code for smaller microproteins.
“The field of microproteins is still so new,” Miller said. “We don’t yet know how many microprotein genes are even functional, and the cost to study 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 detecting SHMOOSE shows the power of integrating big genetic data with molecular and biochemical techniques to discover functional microproteins.”
USC Leonard Davis researchers are leaders in the study of microproteins, particularly those encoded in the mitochondrial genome. In 2003, Cohen and his colleagues were one of three research teams to independently discover the protein humanin, which appears to have protective health effects in Alzheimer’s disease, 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 been the subject of clinical trials for obesity and fatty liver disease.
University of Southern California
Miller, B. et al. (2022) Mitochondrial DNA variation in Alzheimer’s disease reveals a unique microprotein called SHMOOSE. Molecular psychiatry. doi.org/10.1038/s41380-022-01769-3.