Impact Circle Project: Understanding the connection between diabetes and Parkinson’s disease

When given the option of projects to support, Buck Impact Circle members recently pooled their resources and chose one aimed at investigating an intriguing link between diabetes and Parkinson’s disease. The project, which is a joint venture between the Kapahi and Andersen labs, could lead to new therapeutics for age-related diseases starting with Parkinson’s, a progressive neurodegenerative disease that causes muscle rigidity and tremors.

The project, begun in worms, will now move into cell culture and mice – thanks to the help of the Impact Circle, which provides an opportunity for Marin residents to become more intimately engaged with the work being done at the Buck, and to tap into deep regional interest in matters relating to healthy aging. “We are extremely grateful for the Impact Circle support,” said Buck faculty Pankaj Kapahi, PhD. “Scientists appreciate the opportunity to personally interact with donors interested in our research. We look forward to meeting with the Impact Circle regularly to provide updates on our work.” The Impact Circle currently has 18 members. Each year participants donate a minimum of $5,000 to support early- stage research at the Buck.

Here’s what caught the attention of the group this year: Various epidemiological studies suggest that those with diabetes carry a 40 to 80 percent increased risk of developing Parkinson’s, with women and young adults at highest risk.  But the biological mechanisms behind the link have not been understood.  There is no cure for Parkinson’s, which is currently expected to affect 8.7 million individuals worldwide by 2030. 

The project took root in the Kapahi lab where researchers work on understanding the role of nutrition and energy metabolism in lifespan and disease.  One of the projects in the lab focuses on type 2 diabetes and its complications – such as diabetic neuropathy, cardiomyopathy, nephropathy and retinopathy. Many diabetic complications stem from the formation of AGEs (advanced glycation end products). AGEs are toxic molecules which are formed when proteins and lipids become bound after exposures to sugar. 

AGEs affect nearly every cell type and are a normal byproduct of metabolism – and even though they are a factor in aging AGEs are not generally a problem for those who eat a healthy diet.  But the production of AGEs really ramps up when blood sugar is out of control, as it is in diabetes.  Kapahi says those who want to see AGEs form in real time just need to put some meat in a hot skillet. “The browning 

that you see when you sear meat is an example of the AGE-related cross-linking that occurs in proteins,” he said, adding that AGEs are implicated in heart disease, neurodegenerative disorders (including Parkinson’s) as well as diabetic complication. “The cloudiness that occurs in cataracts is also linked to the formation of AGEs,” Kapahi said.  

So what’s the connection between AGEs and Parkinson’s? Working in the nematode worm C. elegans, researchers found that a gene known as DJ-1 produces an enzyme that detoxifies the highly reactive compounds that cause AGEs. When the team realized that mutations in DJ-1 were linked to a familial form of Parkinson’s, Kapahi took the discovery to Buck faculty Julie Andersen, a neuroscientist who studies cell death in Parkinson’s.

Andersen said animals, including humans, who carry mutations in DJ-1 under express the detoxifying enzyme that can clear AGEs. “AGEs are found in the brains of those who have Parkinson’s; they drive the aggregation of the protein alpha-synuclein which causes neurons specific to Parkinson’s to die,” she said. “The finding that links DJ-1 to both Parkinson’s and the formation of AGEs could provide an important link between diabetes and Parkinson’s.”

Fortunately, the molecular pathway connected to DJ-1 is druggable – and early screens of natural compounds have identified several lead candidates that ameliorate the damage due to AGE toxicity. “The hope is to develop a new treatment for Parkinson’s,” said Kapahi. “The research also holds a tantalizing possibility that compounds that target DJ-1 could be valuable in treating a number of age-related diseases.”

In its first two projects, the Impact Circle raised $100,000 each for early-stage projects involving cancer and the aging brain, and Alzheimer’s and aging.  In 2014 the seed monies financed experiments in the Campisi and Andersen labs that led to an NIH grant; in 2015 the support helped scientists in the Bredesen lab publish in the prestigious Journal of Neuroscience.  

“It’s not too late for donors to join this year’s Impact Circle,” said Carlotta Duncan, PhD, the Institute’s Director for Scientific Advancement and the Impact Circle coordinator. “We are still seeking support for this year’s project and there are plenty of opportunities to meet and interact with the dedicated scientists involved in the project.“  For more information on the Impact Circle, email info@buckinstitute.org .

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