Alzheimer’s disease risk linked to the recently discovered protein mutation

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Researchers have discovered a microprotein called SHMOOSE, which appears to play a physiological role in neurodegeneration and its mutation is linked to Alzheimer’s risk. VICTOR TORRES / Stocksy
  • Researchers used multiple methods to analyze mitochondrial genetic data and identify a mitochondrial microprotein associated with Alzheimer’s disease risk.
  • They discovered the SHMOOSE microprotein, which appears to play a physiological role in neurodegeneration.
  • The mutated version of the SHMOOSE microprotein, present in over 20% of Europeans, is linked to a higher risk of Alzheimer’s.
  • The discovery opens up new avenues for detecting, preventing and treating Alzheimer’s disease.

Mitochondria are structures within the cell that convert energy from food into energy that the cell can use. Each cell contains hundreds to thousands of mitochondria. Although most of the DNA is found inside the cell’s nucleus, mitochondria also contain a small amount of DNA, known as mitochondrial DNA.

In the early 2000s, researchers realized that short sections of mitochondrial DNA code for small biologically active proteins (less than 100 amino acids long), now referred to as mitochondrial microproteins. It was called the first mitochondrial microprotein discoveredhuman. “

There is growing evidence that humanin and other similar mitochondrial microproteins play a role in several age-related conditions, including Alzheimer’s disease.

Alzheimer’s disease is the most common type of dementia, characterized by progressive mental deterioration. According to Center for Disease Prevention and Controlin 2020, as many as 5.8 million Americans were living with Alzheimer’s disease.

The Cohen Laboratory at the University of Southern California (USC), one of three laboratories that independently discovered humanin in 2003, has discovered a new microprotein linked to Alzheimer’s risk.

Their latest research, published in the journal of Molecular Psychiatry, revealed that a recently discovered mutation in the “SHMOOSE” microprotein is associated with a higher risk of Alzheimer’s disease in four cohorts. According to the researchers, nearly 1 in 4 individuals with European ancestry have the mutated version of the protein.

dr. Pinchas Cohen, professor of gerontology, medicine, and biological sciences and senior author of the study, said Medical news today:

“The implications aren’t immediate, but we believe them [relatively soon]the SNP SHMOOSE [single nucleotide polymorphism] The genetic variant found in more than 20% of Europeans can guide both the classification of individuals at risk for Alzheimer’s who may benefit from certain preventive measures, and could also inform the selection of medical interventions that will be available in the near future. A little further on, SHMOOSE [protein] analogues may become available as therapeutics for people who carry PNS and develop dementia, in a “precision medicine” approach.

Brendan Miller, Ph.D., first author of the study, studied mitochondrial DNA sequences from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database, looking for small variations in genes called single nucleotide polymorphisms or SNPs. He found that a mutation in a particular mitochondrial SNP (rs2853499) was associated with an increased risk of Alzheimer’s disease and brain atrophy.

dr. Miller and his colleagues then found that the mutated SNP causes a change in a mitochondrial microprotein, which they called “SHMOOSE”. The researchers used a technique called immunoprecipitation to isolate the SHMOOSE microprotein from the mitochondria of nerve cells.

When they analyzed this sample using mass spectrometry, they detected and identified two unique protein fragments from the SHMOOSE microprotein. The researchers reported that this is “the first unique mass spectrometry-based detection of a microprotein encoded by mitochondria to date.”

After identifying a microprotein associated with a higher risk of Alzheimer’s disease, the researchers continued their discovery by carrying out studies in rats and cell culture experiments.

They found that the SHMOOSE microprotein accumulates in the mitochondria of neurons (nerve cells), where it binds to the inner mitochondrial membrane protein mitophilin. The SHMOOSE microprotein appears to act on the brain by affecting mitochondrial gene expression and increasing mitochondrial oxygen consumption. The researchers noted that the mutated SHMOOSE microprotein was less effective in increasing oxygen consumption and affected gene expression differently.

“Dysregulated brain energy associated with mitochondria is one of multiple pathways believed to be important for Alzheimer’s,” said Andrew Saykin, PsyD, ABCN, professor and director of the Center for Neuroimaging and Indiana Alzheimer’s Disease Research Center. MNT.

George Perry, Ph.D., Professor and Semmes Foundation Distinguished University Chair in Neurobiology at the University of Texas at San Antonio, said MNT that this study is “very important as it left the risk of [Alzheimer’s disease] to cell metabolism. There are numerous cell biology and biochemical studies that highlight this […] and find genetic data for further support[s] This view. “

dr. Saykin noted that “with further development and validation there may be implications of this and other microproteins for early diagnosis, longitudinal monitoring and potentially for therapeutic targeting.”

MNT he also discussed the study findings with Tal Nuriel, Ph.D., assistant professor of pathology and cell biology at Columbia University’s Irving Medical Center. dr. Nuriel said MNT that most Alzheimer’s disease-related genetic mutations discovered in the past “are either very rare variants or common variants that confer very little risk.”

He said the mutation, or variant, of the SHMOOSE microprotein “appears to confer a moderate risk for Alzheimer’s disease and is relatively common in the population” and “[this] alone makes it interesting.

dr. Nuriel added that “the fact that this is a microprotein that can theoretically be administered as a therapeutic agent is valuable.” She warned that “there will be a long way to go before any therapy derived from this microprotein can become a reality. Importantly, it is unclear whether this SHMOOSE microprotein would enter the brain if administered subcutaneously or intravenously. And if it does not enter the brain, this would greatly limit its ability to be used therapeutically ”.

Asked about the next step in research after this discovery, Dr. Cohen said MNT, “Our immediate plan is to treat mice that have been designed to develop Alzheimer’s disease with SHMOOSE for several months and evaluate the improvement in their symptoms and performance. We will also work on the development of longer-acting analogues of pep[t]idea.”

The researchers noted in the study that “SHMOOSE is another microprotein of increasing numbers that modifies mitochondrial biology.” According to a recent review, “thousands” of DNA sequences with microprotein-encoding potential are currently unverified or functionally uncharacterized.

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