Newly Discovered Protein Connected to Significant Increase in Risk of Alzheimer’s Disease



A new University of Southern California (USC) Leonard Davis School of Gerontology study found a significant increase in the risk for Alzheimer's disease is linked to a mutation in a minor protein that has recently been discovered. This opens up a new possible therapy route and broadens the list of known gene targets for the illness.

The tiny "microprotein" with the name SHMOOSE is produced by a recently identified gene in the mitochondria of a cell. In four distinct cohorts, a mutation in this gene is associated with a 30% increased risk for Alzheimer's disease and partially inactivates the SHMOOSE microprotein. Nearly 25% of persons with European ancestry, according to the study, have the altered protein.

The most common form of dementia is Alzheimer's. The disease is gradual, starting with mild memory loss and potentially progressing to the loss of communication and environmental awareness. The CDC estimates that 5.8 million Americans will have Alzheimer's disease in 2020.

The researchers found that this previously unknown mutation sets it apart from other proteins linked to Alzheimer's disease due to its great prevalence and significant danger. Very a small number of additional gene variants have been discovered, and they only slightly raised risk by less than 10%. APOE4 is the strongest known genetic risk factor for the condition. Additionally, the microprotein is simple to deliver because it is similar in size to the insulin peptide. This greatly raises the medicinal potential of it.

With SHMOOSE as a target area, this discovery "opens interesting new options for developing precision medicine-based therapeutics for Alzheimer's disease," according to Pinchas Cohen. He is a professor of gerontology, medicine, and biological sciences and the study's senior author. SHMOOSE analogs may be administered to those who have the mutation and produce the mutant protein to treat neurological and other aging-related disorders.

The study's first author is Brendan Miller, a USC neuroscience PhD graduate who graduated in 22. He discovered mitochondrial DNA genetic variants linked to disease risk using big data approaches. Miller and his colleagues identified that the defective gene coded for the SHMOOSE microprotein and started researching its mutated and default forms after investigations suggested a gene mutation raised the risk of Alzheimer's disease, brain atrophy, and energy metabolism. According to the researchers, SHMOOSE is the first microprotein encoded by mitochondrial DNA to have been discovered using both antibodies and mass spectrometry.

It indicates that the microprotein changes the central nervous system's metabolism and energy signaling. It was discovered in the mitochondria of neurons, and indicators for Alzheimer's disease were connected with its levels in cerebrospinal fluid. 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.

The sixth most common cause of death in the US is currently Alzheimer's disease. However, according to the CDC's most recent predictions, the condition may come in third place as a cause of death for seniors, only behind cancer and heart disease. Although there is presently no cure for Alzheimer's, there has been great advancement in the creation and testing of new treatments in recent years.

Miller claims that the results underscore the significance of the relatively young science of microproteins. For years, 20,000 big protein-coding genes have served as the main focus of biology research. However, current technologies have revealed hundreds of thousands more potential genes that encode small microproteins.

Miller said that "the science of microproteins is still so fresh." "We don't yet know how many microprotein genes are even functional, and it would be both expensive and ineffective to research each potential microprotein individually from a list of thousands. The method my coworkers and I used to find SHMOOSE demonstrates the effectiveness of combining huge genomics data with molecular and biochemical approaches to find functional microproteins.

Leaders in the study of microproteins, particularly those encoded in the mitochondrial genome, are USC Leonard Davis researchers. The protein humanin, which seems to have beneficial health effects in Alzheimer's, atherosclerosis, and diabetes, was independently discovered by three research teams in 2003, two of which were led by Cohen and his colleagues. The Cohen Laboratory only recently identified more mitochondrial microproteins, such as small humanin-like peptides, or SHLPs, and a microprotein known as MOTS-c, an exercise-imitating peptide that is currently being tested in clinical trials for obesity and fatty liver.

By UNIVERSITY OF SOUTHERN CALIFORNIA 

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