A mutation in a newly discovered small protein is associated with a substantial increase in the risk for Alzheimer’s disease, according to a new University of Southern California (USC) Leonard Davis School of Gerontology study. This expands the known gene targets for the disease and presents a new potential avenue for treatment.
Called SHMOOSE, the protein is a tiny “microprotein” encoded by a newly discovered gene within the cell’s energy-producing mitochondria. A mutation within this gene partially inactivates the SHMOOSE microprotein and is linked to a 30% higher risk for Alzheimer’s disease across four different cohorts. According to the researchers, almost 25% of people of European ancestry have the mutated version of the protein.
The research was published on September 21 in the journal Molecular Psychiatry.
Both the substantial risk and high prevalence of this previously unidentified mutation differentiate it from other proteins involved in Alzheimer’s disease, according to the researchers. Besides for APOE4 - the most potent known genetic risk factor for the disease - only a limited number of other gene mutations have been identified and these only mildly increased risk by less than 10%. Additionally, because the microprotein is approximately the size of the insulin peptide, it can be easily administered. This significantly increases its therapeutic potential.
“This discovery opens exciting new directions for developing precision medicine-based therapies for Alzheimer’s disease, focusing on SHMOOSE as a target area,” said Pinchas Cohen. He is the senior author of the study and professor of gerontology, medicine and biological sciences. “Administration of SHMOOSE analogs in individuals who carry the mutation and produce the mutant protein may prove to have benefit in neurodegenerative and other diseases of aging.”
Brendan Miller, USC ’22 PhD in neuroscience graduate, is the first author of the study. He used big data techniques to identify genetic variations in mitochondrial DNA associated with disease risk. After analyses revealed a gene mutation increased Alzheimer’s disease risk, brain atrophy, and energy metabolism, Miller and his colleagues discovered that the mutated gene coded for the SHMOOSE microprotein and began investigating its mutated and default forms. SHMOOSE is the first mitochondrial-DNA-encoded microprotein to have been detected using both antibodies and mass spectrometry, according to the researchers.
It appears that the microprotein modifies energy signaling and metabolism in the central nervous system. It was found in mitochondria of neurons and its levels in cerebrospinal fluid correlated with biomarkers of Alzheimer’s disease. A variety of cell culture and animal experiments showed that SHMOOSE alters energy metabolism in the brain in part by inhabiting a crucial part of the mitochondria, the inner mitochondrial membrane.
Alzheimer’s disease is currently ranked as the sixth leading cause of death in the United States. However, recent estimates by the CDC indicate that the disorder may rank third, just behind heart disease and cancer, as a cause of death for older people. Although there is currently no cure for Alzheimer’s disease, there has been significant progress in recent years in developing and testing new treatments.
According to Miller, the importance of the relatively new field of microproteins is highlighted by the findings. For decades, scientists have studied biology mostly by considering a set of 20,000 large protein-coding genes. However, hundreds of thousands more possible genes that encode tiny microproteins have been brought to light by modern technologies.
“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 just too expensive and inefficient. The approach my colleagues and I used to detect SHMOOSE shows the power of integrating big genetics data with molecular and biochemical techniques to discover functional microproteins.”
USC Leonard Davis scientists are leaders in the study of microproteins, especially those coded within the mitochondrial genome. In 2003, Cohen and his colleagues were one of the three teams of researchers to independently discover the protein humanin, which appears to have protective health effects in Alzheimer’s, atherosclerosis, and diabetes. In just the past few years, the Cohen Laboratory discovered several other mitochondrial microproteins, including, small humanin-like peptides, or SHLPs, and a microprotein called MOTS-c, an exercise-mimetic peptide that has entered clinical trials for obesity and fatty liver.
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