Study finds microproteins linked to Alzheimer’s risk

(Elish Turner | The Daily Trojan)

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

The newly discovered protein, called SHMOOSE, is encoded by a gene located within the cell’s mitochondria, which is responsible for the cell’s energy production. A mutation within this gene, which inhibits the activity of the partial SHMOOSE protein, is associated with a 30% increased risk of developing Alzheimer’s disease for an individual. The modified version of the protein was reported to have appeared in nearly a quarter of people of European ancestry.

Brendan Miller, a 2022 doctoral graduate who studied neuroscience and the study’s first author, relied on big data techniques to identify genetic variations associated with disease risk, after analyzes revealed that mutations are associated with an increased risk of Alzheimer’s disease, brain atrophy and energy metabolism.

The researchers began by studying the variant and hypothetical forms of the gene and found that SHMOOSE is the first microprotein encoded in mitochondria and DNA to be detected using both antibodies and mass spectrometry.

One of the biggest hurdles in the research process, Miller said, is the vast amount of data the researchers had to gather to come up with these findings. Miller described this “big data” as taking up “terabytes” of storage, and containing research obtained from dozens of individuals. His team was able to overcome this through the use of new and advanced technology, which allowed them to make discoveries that were not possible in any other way.

“Over the past 10 years, computational power has grown exponentially. That means you will see a lot of rapid discoveries in medicine and biology.” “At USC, we have the infrastructure, and we have a lot of talented computing scientists to help us with that.”

Miller said the ability to process and understand big data was essential to the success of this project.

“The big challenge starts with hundreds of potential genetic targets and narrows them down to a single target,” Miller said. “The way we did this was [by] Perform lots of genetics data and omics data from similar individuals with different data types. “

The study highlights the importance of the emerging field of microproteomics studies. Microprotein, a small protein encoded from a small open reading frame, appears to modulate energy signaling and metabolism in the central nervous system. A variety of studies have found microproteins in the 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, you’ll find hundreds of thousands of them, [which] “It creates a whole new dimension of things to discover,” said Pinchas Cohen, professor of gerontology, medicine and biological sciences and lead author of the study.

There is currently no approved Alzheimer’s drug developed based on microproteins, while protein or peptide-related therapies have been used to treat diabetes, heart disease, and some other chronic diseases. Thus, the therapeutic potential of microproteins in cases of Alzheimer’s disease has been exciting news for many researchers in this field.

Helena Chang Choi, principal and professor of neuroscience at Keck School of Medicine, said the research paper is “very rich” and has a huge potential impact on understanding the causes of Alzheimer’s disease.

“We’re getting a little closer to immunological approaches with monoclonal antibodies…[and] “Antibodies against amyloid proteins, but there are no peptide-specific treatments,” Choi said.

In general, Cohen said, researchers are cautiously optimistic about the study’s therapeutic potential, and it’s still too early to consider applying the study’s findings to clinical research. Cohen said he hopes the team can use standard mouse models of Alzheimer’s disease and demonstrate that SHMOOSE has benefits in treating Alzheimer’s disease.

Then, Cohen noted, the team might select individuals with the SHMOose mutation to conduct the research, which would lend precision medicine approaches.

“The issue is that Alzmeer’s disease is very heterogeneous. [It’s] It’s not really one specific case, it’s multiple conditions, each the result of different genetic sensitivities, and they all exist in a similar way,” Cohen said. “That’s why I think treatments that will focus on the underlying genetic abnormality, also known as precision medicine approaches, will be more effective. .”

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