In a new study, researchers from the University of Southern California (USC) report that a mutation in a tiny protein has been linked to a higher risk of developing Alzheimer’s disease. This adds to the list of known gene targets for the disease and suggests a new way to treat it.
The protein, which goes by the name SHMOOSE, is a very small “microprotein” that is encoded by a gene that was just recently found within the energy-producing mitochondria of a cell. In four distinct cohorts, a mutation in this gene results in a 20–50% increased risk for Alzheimer’s disease and partially inactivates the SHMOOSE microprotein. Researchers say a fourth of Europeans carry the mutated protein.
This study was published in Molecular Psychiatry today.
The researchers say that this mutation is different from other proteins that are involved in Alzheimer’s disease because it poses a big risk and is very common. Only a few additional gene variants have been discovered, and they only slightly raised the risk by less than 10%. APOE4 is the most significant known genetic risk factor for the condition. Also, since the microprotein is about the same size as the insulin peptide, it is easy to give, which makes it more useful as a medicine.
Pinchas Cohen, professor of gerontology, medicine, and biological sciences and senior author of the paper, noted that this finding “opens exciting new directions for developing precision medicine-based therapies for Alzheimer’s disease, focusing on SHMOOSE as a target area.” SHMOOSE analogues may be administered to those who have the mutation and produce the mutant protein to treat neurological and other aging-related disorders.
Brendan Miller, who got his PhD in neuroscience in 2022 and was the study’s first author, used big data techniques to find genetic changes in mitochondrial DNA that increased the risk of disease. 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 studying its mutated and default forms.
According to the researchers, SHMOOSE is the first microprotein encoded by mitochondrial DNA to be discovered using both antibodies and mass spectrometry.
The microprotein appears to alter central nervous system energy signalling and metabolism. It was discovered in the mitochondria of neurons, and its levels in cerebrospinal fluid were linked to Alzheimer’s disease indicators. Numerous cell culture and animal studies revealed that SHMOOSE changes the brain’s energy metabolism in part by residing in the inner mitochondrial membrane, which is an essential component of the mitochondria.
Miller noted that the results demonstrate the significance of the relatively recent subject of microproteins. For years, 20,000 big protein-coding genes have served as the main focus of biology research. However, hundreds of thousands more possible genes that encode tiny microproteins have been brought to light by new technology.
“The field of microproteins is still so new,” Miller added.
“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.”
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