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.

An emerging field of study

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.

Reference: “Mitochondrial DNA variation in Alzheimer’s disease reveals a unique microprotein called SHMOOSE” by Brendan Miller, Su-Jeong Kim, Hemal H. Mehta, Kevin Cao, Hiroshi Kumagai, Neehar Thumaty, Naphada Leelaprachakul, Henry Jiao, Joan Vaughan, Jolene Diedrich, Alan Saghatelian, Thalida E. Arpawong, Eileen M. Crimmins, Nilüfer Ertekin-Taner, Meral A. Tubi, Evan T. Hare, Meredith N. Braskie, Léa Décarie-Spain, Scott E. Kanoski, Francine Grodstein, David A. Bennett, Lu Zhao, Arthur W. Toga, Junxiang Wan, Kelvin Yen and Pinchas Cohen, 21 September 2022, Molecular Psychiatry.
DOI: 10.1038/s41380-022-01769-3

Additional co-authors include Su-Jeong Kim, Hemal H. Mehta, Kevin Cao, Hiroshi Kumagai, Neehar Thumaty, Naphada Leelaprachakul, Henry Jiao, Thalida E. Arpawong, Eileen Crimmins, Meral A. Tubi, Evan T. Hare, Meredith N. Braskie, Léa Décarie-Spain, Scott E. Kanoski, Lu Zhao, Arthur W. Toga, Junxiang Wan, and Kelvin Yen of USC; as well as Joan Vaughan, Jolene Diedrich, and Alan Saghatelian of the Salk Institute for Biological Studies; Nilüfer Ertekin-Taner of the Mayo Clinic; and Francine Grodstein and David A. Bennett of the Rush University Medical Center.

The study was supported by NIH grants P30AG10161, P30AG072975, R01AG15819, R01AG17917, U01AG61356, R01AG069698, RF1AG061834, R01AG068405, P30AG068345, P01AG055369, DK118402, F31 AG059356, and T32 AG00037; as well as The Quebec Research Funds Postdoctoral Fellowship. Intellectual property related to SHMOOSE has been filed by the University of Southern California.