Study finds microprotein correlated to Alzheimers risk – Daily Trojan Online

(Aylish Turner | Daily Trojan)

A mutation in a newly discovered microprotein might lead to a significant risk for Alzheimers disease, according to research from the Leonard Davis School of Gerontology. The discovery expanded the gene target to treat the disease and provided a new potential therapeutic solution to the incurable disease.

The newly-discovered protein, named SHMOOSE, is encoded by a gene that exists within the cells mitochondria, which is responsible for cells energy production. A mutation within this gene, which partially inactivates the SHMOOSE microprotein, is associated with a 30% increase in ones risk of developing Alzheimers disease. The mutated version of the protein has reportedly appeared within nearly a quarter of people of European ancestry.

Brendan Miller, a 2022 doctoral graduate who studied neuroscience and the studys first author, relied on big data techniques to identify genetic variations associated with disease risk, after analyses revealed that mutations are linked to increased risk of Alzheimers, brain atrophy and energy metabolism.

Researchers began studying the genes mutated and default forms and found that SHMOOSE is the first mitochondrial-DNA-encoded microprotein to be detected using both antibodies and mass spectrometry.

Miller said one of the biggest obstacles in the research process was the sheer amount of data that researchers had to compile to make these findings. Miller described this big data as taking up terabytes of storage, containing research gleaned from dozens of individuals. His team was able to overcome this by utilizing new and advanced technology, which allowed them to make discoveries not otherwise possible.

Computational power over the last ten years has grown exponentially. With that means youre going to see in the field of medicine and biology a lot of rapid discoveries, Miller said. At USC, we have infrastructure, and we have a lot of talented computational scientists to help us with that.

Being able to manipulate and understand big data was essential for the success of this project, Miller said.

The big challenge is starting from hundreds of potential gene targets and narrowing them down to one, Miller said. The way we did this was [by] implementing a lot of genetics data and omics data from similar individuals with different data types.

The study highlights the importance of the emerging field of microprotein studies. Microprotein, a small protein encoded from a small open reading frame, appears to modify energy signaling and metabolism in the central nervous system. A variety of studies have found microproteins in mitochondria of neurons and showed that SHMOOSE alters energy metabolism in the brain, in part by inhibiting the inner mitochondrial membrane.

When you look at microproteins, there are many hundreds of thousands of them, [which] creates a whole new dimension of things that need to be discovered, said Pinchas Cohen, a professor of gerontology, medicine and biological sciences and the senior author of the study.

There is currently no approved medicine for Alzheimers disease developed based on microproteins, while microprotein- or peptide-related treatments have been employed in treatments of diabetes, heart diseases and some other chronic illnesses. The therapeutic potential of microproteins in Alzheimers cases was thus exciting news for many researchers in the field.

Helena Chang Chui, chair and professor of neurology at Keck School of Medicine, said the paper is very rich and has significant potential impact for understanding the causes of Alzheimers.

Were getting a little bit closer with immunological approaches with monoclonal antibodies[and] antibodies against amyloid proteins, but theres been no particular no peptide treatments, Chui said.

Researchers are, on the whole, cautiously optimistic about the therapeutic potential of the study, Cohen said, and it is still too early to contemplate applying the findings of the study into therapeutic research. Cohen said he hopes that the team could use standard mouse models of Alzheimers and demonstrate that SHMOOSE does have benefits on the treatment of Alzheimers disease.

Then, as Cohen implied, the team might pick individuals who have the SHMOOSE mutation to do the research, which will lend to the precision medicine approaches.

The issue is that Alzhmeimers disease is very heterogeneous. [Its] not really one specific condition, its multiple conditions, each being a result of various genetic susceptibilities, that all present in a similar way, Cohen said. Thats why I believe that treatments that will be focused on the primary genetic abnormality, also known as precision medicine approaches, will be more efficacious.

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Study finds microprotein correlated to Alzheimers risk - Daily Trojan Online