A mutation in the small protein SHMOOSE is linked with increased Alzheimer’s risk and highlights a possible target for treatment.

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.

Alzheimer’s disease is the most prevalent type of dementia. It’s a progressive disease beginning with mild memory loss and possibly leading to loss of the ability to carry on a conversation and respond to the environment. According to the CDC, in 2020, as many as 5.8 million Americans were living with Alzheimer’s disease.

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.”

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