Newly discovered protein connected to Alzheimer’s disease risk

A mutation in a newly discovered small protein is linked to a significant increase in Alzheimer’s risk, according to a new USC study, expanding known gene targets for the disease and offering a new potential treatment avenue.

The protein, called SHMOOSE, is a tiny “microprotein” encoded by a newly 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% higher risk of Alzheimer’s disease in four different cohorts. According to the researchers, almost a quarter of people of European descent have the mutated version of the protein.

The research appears in the journal Wednesday, September 21 Molecular Psychiatry.

The researchers say both the significant risk and high prevalence of this previously unidentified mutation sets it apart from other proteins implicated in Alzheimer’s disease. Apart from APOE4 – the strongest known genetic risk factor for the disease – only a limited number of other gene mutations have been identified and these only slightly increased the risk by less than 10%. In addition, because the microprotein is roughly 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, with a focus on SHMOOSE as a target area,” said Pinchas Cohen, professor of gerontology, medicine and life sciences and senior author of the study. “Administering SHMOOSE analogs to individuals who carry the mutation and produce the mutated protein may prove beneficial in neurodegenerative and other diseases of aging.”

Brendan Miller, ’22 Ph.D. in neuroscience and first author of the study, used big data techniques to identify genetic variations in mitochondrial DNA that are linked to disease risk. After analyzes revealed that a gene mutation increased Alzheimer’s risk, brain atrophy and energy metabolism, Miller and his colleagues discovered that the mutated gene encoded the SHMOOSE microprotein and began studying its mutated and standard forms. The researchers stated that SHMOOSE is the first mitochondrial DNA-encoded microprotein to be detected using both antibodies and mass spectrometry.

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 biomarkers of Alzheimer’s disease. A large number of cell culture and animal experiments showed that SHMOOSE changes the energy metabolism in the brain, among other things, by inhabiting a crucial part of the mitochondria, the inner mitochondrial membrane.

An emerging subject

Miller said the results underscore the importance of the relatively new field of microproteins. For decades, scientists have studied biology primarily through a set of 20,000 major protein-coding genes. However, new technology has revealed hundreds of thousands of potential genes encoding 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 of examining one potential microprotein individually from a list of thousands is simply too expensive and inefficient. The approach my colleagues and I used to discover SHMOOSE demonstrates the power of integrating large genetic data with molecular and biochemical techniques to discover functional microproteins.”

USC Leonard Davis researchers are at the forefront of research into microproteins, particularly those encoded in the mitochondrial genome. In 2003, Cohen and his colleagues were among three research teams that independently discovered the protein humanin, which appears to have protective effects in Alzheimer’s disease, atherosclerosis and diabetes. In recent years, the Cohen lab 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 against obesity and fatty liver.