- The researchers used multiple methods to analyse mitochondrial genetics data and identify a mitochondrial microprotein associated with Alzheimer’s risk.
- They discovered the SHMOOSE microprotein, which appears to play a physiological role in neurodegeneration.
- The mutant version of the SHMOOSE microprotein, which is found in over 20% of Europeans, is associated with a higher risk of Alzheimer’s disease.
- The finding opens up new ways of 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 DNA is in the cell nucleus, mitochondria also contain a small amount of DNA known as mitochondrial DNA.
In the early 2000s, researchers discovered that short sections of mitochondrial DNA encode small (less than 100 amino acids long), biologically active proteins that are now referred to as mitochondrial microproteins. The first mitochondrial microprotein discovered was called “humanin.”
There is increasing evidence that humanin and other similar mitochondrial microproteins play a role in various age-related diseases, including Alzheimer’s disease.
Alzheimer’s disease is the most common type of dementia, which is characterized by progressive mental deterioration. According to the CDC, up to 5.8 million Americans were living with Alzheimer’s disease in 2020.
The Cohen Laboratory at the University of Southern California (USC), one of the three laboratories that independently discovered humanine in 2003, has discovered a new microprotein that is linked to the risk of Alzheimer’s disease.
Her latest research, published in the Journal of Molecular Psychiatry, revealed that a mutation in the newly discovered “SHMOOSE” microprotein in four cohorts is associated with a higher risk of Alzheimer’s disease. According to the researchers, almost 1 in 4 people of European descent have the mutant version of the protein.
Dr. Pinchas Cohen, professor of gerontology, medicine and life sciences and lead author of the study, told Medical News Today:
“The implications are not immediate, but we believe that [relatively soon] the SHMOOSE SNP [single nucleotide polymorphism] A genetic variant found in over 20% of Europeans can include both the classification of people at risk of Alzheimer’s who could benefit from specific prevention measures and the Influence the selection of medical interventions that will be available in the near future. A little further ahead, SHMOOSE [protein] analogs could be available as therapeutics for people who carry the SNP and develop dementia, using a “precision medicine” approach.
Study discovers mutant protein
Brendan Miller, Ph.D., lead author of the study, examined mitochondrial DNA sequences from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database and looked 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 a higher risk of Alzheimer’s and brain atrophy.
Dr. Miller and his colleagues then discovered that the mutant SNP causes a change in a mitochondrial microprotein that they called “SHMOOSE.” The researchers used a technique called immunoprecipitation to isolate the SHMOOSE microprotein from the mitochondria of nerve cells.
When analyzing this sample using mass spectrometry, they discovered 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 mitochondrial-encoded microprotein so far.”
Microprotein and Alzheimer’s Disease
After the researchers identified a microprotein associated with a higher risk of Alzheimer’s disease, they followed up their discovery with studies on rats and cell culture experiments.
They found that the SHMOOSE microprotein accumulates in the mitochondria of neurons (nerve cells) and binds there to the inner mitochondrial membrane protein mitofilin. The SHMOOSE microprotein appears to act on the brain by influencing mitochondrial gene expression and increasing mitochondrial oxygen consumption. The researchers found that mutant SHMOOSE microprotein was less effective in increasing oxygen consumption and affected gene expression differently.
“Dysregulated mitochondrial-associated brain getics is one of the many pathways that are thought to be important for Alzheimer’s disease,” Andrew Saykin, PsyD, ABCN, professor and director of the Center for Neuroimaging and Indiana Alzheimer’s Disease Research Center, told MNT.
George Perry, Ph.D., professor and chair at the Semmes Foundation Distinguished University of Neurobiology at the University of Texas at San Antonio, told MNT that this study is “very important as it links the risk of [Alzheimer’s disease] to cell metabolism. There are numerous cell biology and biochemical studies that highlight this […] and finding genetic data further supports this view.”
Alzheimer’s prevention and treatment
Dr. Saykin noted that “with the advancement and validation, effects of this and other microproteins on early detection, longitudinal monitoring, and potentially for therapeutic targeting.”
MNT also discussed the results of the study with Tal Nuriel, Ph.D., assistant professor of pathology and cell biology at Columbia University’s Irving Medical Center. Dr. Nuriel told MNT that most gene mutations associated with Alzheimer’s disease discovered in the past “are either very rare variants or common variants that pose a very low risk.”
He said the mutation or variant in the SHMOOSE microprotein “appears to pose a moderate risk of Alzheimer’s disease and is relatively common among the population,” and “[that] alone makes it interesting.”
Dr. Nuriel added that “the fact that it is a microprotein that can theoretically be given as a therapeutic agent is valuable.” He warned that “there will be a very long way to go before therapy derived from this microprotein could become a reality. It is important that it is unclear whether this SHMOOSE microprotein would reach the brain if administered subcutaneously or intravenously. And if it doesn’t get into the brain, it would severely limit its ability to be used therapeutically.”
When asked about the next research step following this discovery, Dr. Cohen told MNT: “Our immediate plan is to treat mice developed to develop Alzheimer’s disease with SHMOOSE over several months and to assess the improvement of their symptoms and performance. We will also work on developing longer-acting analogs of the pep [t] ide.”
In the study, the researchers found that “SHMOOSE is another microprotein in a growing number that alters mitochondrial biology.” According to a recent review, “thousands” of DNA sequences with microprotein-coding potential are currently not verified or functionally characterized.