Researchers say ‘SHMOOSE’ microprotein linked with high risk of Alzheimer’s

Researchers from the University of Southern California (USC) have discovered a microprotein that could potentially increase the risk of Alzheimer’s disease, if mutated. 

Microproteins are tiny proteins in our body that help cells respond better to hormones and proteins. They also remove free radicals and aid cell growth. As a natural body response, microproteins deplete with age. 

Researchers led by Dr Pinchas Cohen identified a crucial microprotein – SHMOOSE – linked to Alzheimer’s in their study published on September 21. 

They found that a mutation in the DNA of the mitochondria inactivates the microprotein SHMOOSE. This increases the risk of Alzheimer’s by 20-50%. Mitochondria are energy factories of the cells and possess their own DNA, which is different from the DNA of the cell; they play a vital role in keeping the neurons alive.  

According to a statement, the microprotein SHMOOSE appears to modify energy signalling and the metabolism in the central nervous system. The mutation increased not only the risk of Alzheimer’s but also brain cell death (atrophy). 

Dr Cohen and his team used a large dataset comprising 6000 samples of people with Alzheimer’s disease from four undisclosed regions. Additionally, they analysed 20,000 samples from the UK Biobank neuroimaging data. The team’s investigation included genome-wide association studies, neuroimaging, transcriptomics, mass spectrometry and antibodies to detect the coded microprotein.  

The team discovered that a quarter of the samples with European ancestry carried the gene mutation in the mitochondrial DNA.  

Until now, the gene APOE4 was known to be the highest genetic risk contributor (10%) for Alzheimer’s. However, SHMOOSE increases the risk factor by two to five times.  

“Our studies show the power of multi-disciplinary collaborations from genetics epidemiology, biochemistry, molecular biology, and neuroscience — through these integrated techniques, we were able to annotate a previously missed gene. Similar approaches might be used in the future to annotate current parts of the genome that don’t have a known function,” wrote Leigh Hopper, spokesperson for USC, in an email. 

This study expands the knowledge of gene targets for treating Alzheimer’s disease.  

“This discovery opens exciting new directions for developing precision medicine-based therapies for Alzheimer’s disease, focusing on SHMOOSE as a target area,” Dr Cohen, professor of gerontology, medicine and biological sciences and senior author of the study, said in the statement.  

SHMOOSE is approximately as big as the insulin molecule. As such, the researchers envision that it has the potential to be administered as a treatment for neurodegenerative diseases – with the same ease as insulin is given for diabetes.  

Dr Cohen’s lab has previously been associated with unravelling microproteins to understand diabetes and age-related illnesses. “The field of microproteins is still so new, we don’t yet know how many microprotein genes are even functional,” Brendan Miller, first author, in the statement said.