A newly discovered gene for a protein called SHMOOSE is found to raise Alzheimer’s risk by 30 percent — the most substantial risk factor characterized since the disease’s best known genetic risk factor, APOE4.
The hunt for the genetic causes of Alzheimer’s is underway. But there are more than 20,000 genes encoded in our DNA — and that’s a lot of potential culprits to sift through. People who are paying close attention to their genetic risk for Alzheimer’s may have even heard that some genes cause an early-onset form of the disease: PSEN1, PSEN2 and APP, which alone account for five percent of total cases of Alzheimer’s. Having one of these genes means a near-guarantee (though there are some exceptions) of developing early-onset Alzheimer’s within one’s lifetime. Then there is APOE4. One copy of this mutation can more than double one’s chances of developing Alzheimer’s within their lifetime (though, again, there are some exceptions).
Meanwhile, there are many genes that are considered smaller-scale saboteurs. As they tweak the function of human proteins just a little bit, they impair some healthy functions, upping someone’s risk of Alzheimer’s dementia by less than 10 percent. These smaller risk factors are being discovered on the regular. But genes or variants that are considered majorly influential — at the APOE4 level — don’t come along very often. As of this month, there is a new one on the list.
Researchers at the University of Southern California discovered a gene encoding a protein called SHMOOSE, which proves to be the second-greatest genetic risk factor for the disease. In September 2022, the team published their findings in the journal Molecular Psychiatry, revealing that a genetic variant that impairs the SHMOOSE protein increases the risk of developing Alzheimer’s by 30 percent.
When SHMOOSE isn’t working correctly, it may negatively impact metabolism and energy production in the brain. Since the protein is small — the same size as insulin — the researchers surmise it could be synthesized in a lab and tested as a target for new treatments.
“This discovery opens exciting new directions for developing precision medicine-based therapies for Alzheimer’s disease, focusing on SHMOOSE as a target area,” Pinchas Cohen, the senior author of the study and professor of gerontology, medicine and biological sciences at the University of Southern California, said. “Administration of SHMOOSE analogs in individuals who carry the mutation and produce the mutant protein may prove to have benefit in neurodegenerative and other diseases of aging.”
What makes SHMOOSE different from other genes related to Alzheimer’s risk?
APOE4 is found in a general compartment within the center of a cell. But unlike APOE4, SHMOOSE is located in the mitochondria — the energy production factories that power all the cells in the human body. Since the job of the mitochondria is so important, mitochondria carry a small set of their own genes, separate from the rest of the genome, which are passed down maternally. For this reason, the researchers say, the SHMOOSE protein was overlooked for a long time. But its unexpected location wasn’t the only thing that obscured its existence.
For a long time, scientists thought a protein needed to be a certain length in order to fold up and do something useful in the body. As a result, when scientists looked for genes, they searched DNA for instructions to build large proteins, ignoring the existence of the very small ones. However, proteins can be very small — scientists creatively named them microproteins — and finding the instructions for these microproteins is akin to looking for a needle in a haystack.
The search for Alzheimer’s microproteins
The research team narrowed their search by first looking at genetic variants associated with Alzheimer’s risk in the mitochondrial DNA. Then they could check to see whether any of these variants were located on a potential gene. They found one variant in a new gene that produced the microprotein SHMOOSE.
Then, they found that the levels of SHMOOSE in the cerebrospinal fluid were correlated with age, tau levels and white matter volume in the brain. Looking across four large genetic biobanks, the researchers successfully linked SHMOOSE to a 30-percent higher rate of developing Alzheimer’s disease within a person’s lifetime.
How could this discovery impact Alzheimer’s?
“The field of microproteins is still so new,” said first author Brendan Miller, PhD.
Nonetheless, this study reveals that there may be other hidden risk factors for developing dementia. Exploring how these risk factors interact with our biology could open up new avenues for treatments.