Mitochondrial DNA mutation may extend life in Alzheimer’s gene carriers

A new direction in drug discovery.


The USC Leonard Davis School of Gerontology’s research team has discovered a genetic mutation in a small mitochondrial protein that may prolong life, preserve cognitive function, and provide protection against Alzheimer’s disease in people with the APOE4 gene, significantly raising the risk of Alzheimer’s.

In a study involving centenarians, researchers working with academics at Albert Einstein College of Medicine identified a variation affecting humanin, a mitochondrial microprotein. This variation, called P3S-humans, was discovered to be more prevalent in those who survived to be 100 years old even though they carried the APOE4 gene, which is associated with early death and Alzheimer’s disease.

Subsequent investigation showed that APOE4 carriers’ P3S variation appeared to protect cognitive function. This variant is mainly seen among people of Ashkenazi Jewish origin and is uncommon in the broader population. Participants from the Einstein Longevity Genes Project, which studies more than 500 healthy centenarians, near-centenarians, and their progeny, were included in the study.

This work clarifies the role of resilience genes in extending life expectancy. It helps to explain why some individuals with a high risk of Alzheimer’s disease do not develop the condition. It also provides a fresh avenue for investigating treatments based on microproteins in the mitochondria.

Using mice genetically modified to express human APOE4, the researchers could validate the direct binding and stabilizing effects of P3S-human on the pathogenic APOE4 protein and see the development of an Alzheimer-like disease. It was discovered that giving these mice the P3S microprotein decreased the amount of amyloid-beta accumulated in their brains. The buildup of amyloid-beta is a defining feature of Alzheimer’s disease.

Senior author Pinchas Cohen, distinguished professor of gerontology and biological sciences and dean of the USC Leonard Davis School, has investigated the potential effects of different mitochondrial small genes on aging. His team found ten microproteins, which have been in the vanguard of the investigation. One of them, MOTS-c, is presently undergoing clinical trials as a treatment for obesity.

Dr. Cohen’s lab has recently made several discoveries, including the identification of the microprotein SHLP2, which protects against Parkinson’s disease, and the description of SHMOOSE, another microprotein linked to Alzheimer’s disease, in 2022. Building on their earlier studies on mitochondria, this latest finding represents a breakthrough in microprotein discovery, precision health, and longevity science.

The team behind the current study, led by Brendan Miller, a postdoctoral investigator at the Salk Institute and a former doctorate student in Dr. Cohen’s group, identified P3S, a rare human variant most frequently detected in Ashkenazi centenarians. This variation, which changes the third amino acid from proline to serine, was present in about 12% of Ashkenazi centenarians. In contrast, among other European and non-European heritage populations, the frequency of human P3S was less than 0.2%.

By giving the protein to mice with humanized APOE4 genes, mice genetically modified to develop Alzheimer’s disease, the researchers could examine the effects of human P3S in greater detail. The mice’s brains had much lower levels of amyloid-beta after receiving human P3S treatment. Amyloid-beta levels were somewhat reduced by human standard treatment, while human P3S functioned better. Further in-lab and computational analysis demonstrated that the small structural variations in human P3S enabled it to bind to APOE4 more efficiently, increasing amyloid-beta absorption and clearance.

Miller said, “This human P3S, when made by mitochondria, actually binds the protein product of APOE4 very tightly. This seems to help clear away harmful amyloid-beta, which builds up in the brains of people with Alzheimer’s. Our experiments showed that this protein variant could be why some people with the risk gene avoid Alzheimer’s and maintain good brain health into old age.”

The findings highlight the need for more research into how interactions between nuclear and mitochondrial DNA affect aging. They also provide a fresh perspective on how individuals with the APOE4 gene may be able to fend off prevalent age-related illnesses like Alzheimer’s. In the end, according to the researchers, this finding provides additional therapy options for people who are susceptible to age-related illnesses like Alzheimer’s disease.

Cohen said, “Going forward, since human P3S is a microprotein, it could serve as a template for drug design. Microproteins are much smaller than typical proteins, providing advantages for drug development. Additionally, since we understand where human P3S binds to the protein product of APOE4, designing small molecules could be a viable strategy.”

Journal Reference:

  1. Brendan Miller, Su-Jeong Kim, Kevin Cao et al. Humanin variant P3S is associated with longevity in APOE4 carriers and resists APOE4-induced brain pathology. Aging Cell. DOI: 10.1111/acel.14153
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