SRI researchers study the cells of the long-living rodent to find new drug targets for Alzheimer’s, Parkinson’s, and other neurodegenerative disorders.
Neurodegenerative diseases such as Alzheimer’s and Parkinson’s affect millions of people worldwide and there are currently no effective treatments for them. But researchers at SRI are hoping the naked mole rat — a curiously long-lived rodent from east Africa — holds the key to new drug targets that will help scientists treat, and even cure, difficult diseases.
“Part of what prevents the development of effective therapies is the lack of drug targets for those diseases,” said Danuta Sastre, Program Director in SRI’s Biosciences division. “Our goal is to interrogate the function of every gene in the naked mole rat that is resistant to age-related declines in health. The hope is that we can find new targets that other methods haven’t been able to identify.”
Naked mole rats are unusual in a number of ways. The hairless rodents live in underground colonies with a single reproducing queen — a lifestyle that is closer to that of ants or bees than typical mammals. They have very low rates of neurodegenerative disorders and cancer (it’s even challenging for researchers to give them cancer intentionally) and despite being about the same size as a mouse, they live about ten times longer.
“A mouse can live up to four years, and that’s an old mouse,” Sastre said. “Mole rats have been recorded as old as 39 years. That’s about the equivalent of a human supercentenarian — someone who is 110 years old.”
Unlocking the secrets of age-related diseases
Naked mole rats remain youthful as they age, somehow avoiding joint trouble, heart problems, and, most importantly for Sastre’s research, the buildup of damaged or misfolded proteins. In humans, aggregations of non-functional proteins, which can disrupt cell function, are markers of many age-related and neurodegenerative diseases. Even in a healthy person, the ability to remove these garbage proteins declines as we get older. With Alzheimer’s, Parkinson’s, and other similar diseases, these accumulations happen faster and grow larger.
“With the help of the naked mole rat, we hope to discover a genetic blueprint to stave off serious age-related diseases.” — Danuta Sastre
As a part of the Advanced Cellular Target Identification and Validation Engine, or ACTIVE program, Sastre and her colleagues are studying cells to understand why these protein aggregations don’t occur in naked mole rats. Humans and naked mole rats share many common genes and SRI researchers believe that answers will provide a roadmap for restoring cell function in humans.
“We’re working on finding shared mechanisms that all cells rely on to care for protein aggregates,” Sastre said. “If we study how naked mole rats deal with this cellular garbage, the results may be translatable to the diseases that share that accumulation.”
The science of cells
The researchers have spent several years culturing naked mole rat cells and developing custom gene-editing reagents to manipulate individual genes within cells. Vanessa Vanuy, a research associate at SRI, led the process of making these reagents and Paula Kempe, a postdoctoral researcher at SRI, has been characterizing the cell lines. Soon, Sastre and her team will begin knocking out each gene in the naked mole rat cells one by one.
If various proteins accumulate after a gene is eliminated, that is a strong indicator that this gene may help prevent protein aggregation and might be a good target for new drugs designed to inhibit unwanted protein buildup in human cells. The research team hopes to discover treatments that will help people as quickly as possible.
“With SRI’s long history in drug development, we have the expertise to identify and develop a drug quickly and deliver it to the market,” Sastre said. “Our team at SRI is passionate about creating new therapies for incurable diseases. And, with the help of the naked mole rat, we hope to discover a genetic blueprint to stave off serious age-related diseases.”
