$400K award will go to explore brain-gut connection in Parkinson’s

US neuroscientist wins Department of Defense grant for study

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by Steve Bryson, PhD |

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The U.S. Department of Defense has awarded $400,000 to an Augusta University (AU) neuroscientist to research a possible brain-gut connection in Parkinson’s disease.

Danielle Mor, PhD, from the Medical College of Georgia at AU, will use the two-year Early-Investigator Research Award to explore whether Parkinson’s starts in the gut.

Specifically, Mor will use a roundworm animal model to investigate how toxic alpha-synuclein protein clumps — which build up in Parkinson’s — may form in the gut and travel to the brain and cause disease.

Her research team also will screen large numbers of approved medicines to assess their ability to block nerve cell damage caused by alpha-synuclein clumping in the gut. The goal is to identify those treatments with the potential to block the gut-brain connection and prevent Parkinson’s disease.

“This is now a hot area of research,” Mor, a faculty member in the Medical College of Georgia’s department of neuroscience and regenerative medicine, said in a university news story. “I think we need to be intervening at the stage of the gut, and that is honestly pretty exciting.”

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In Parkinson’s, the accumulation of toxic alpha-synuclein clumps are thought to contribute to the death of neurons in the brain that produce the chemical signaling molecule dopamine, leading to characteristic disease symptoms.

Emerging evidence suggests inflammation in the gut can trigger alpha-synuclein misfolding and clumping, and these so-called aggregates have been detected in gut tissue of people with early Parkinson’s.

Such findings suggest that alpha-synuclein may form clumps in gut neurons, then spread to the brain via connections between neurons in the enteric nervous system, which controls many gut functions, and the brain.

Mor chose the validated C. elegans model, which are transparent tiny roundworms that share about half of their genes with humans. Because these worms also have many of the same types of neurons, including those that produce dopamine, and an enteric nervous system, their short lifespan — the worms typical live 2-4 weeks — facilitates the rapid study of the neurological condition.

In previous work, Mor fed a toxic form of alpha-synuclein to the worms and saw it spread, triggering the death of dopamine-producing neurons.

“I have seen that it spreads to their different body tissues, and I have seen the neurons degenerating and I have seen the [worms] have motor problems in a matter of days,” Mor said.

The new funding will support research focusing on the brain-gut connection, specifically how alpha-synuclein travels from the gut to the brain to cause cognitive impairment. That is a common nonmotor symptom seen in the later stages of Parkinson’s.

“We are modeling gut-to-brain alpha-synuclein transmission, which we believe is one potential way that this disease occurs in humans and now we will test cognitive function,” Mor said.

To assess cognitive function, Mor will mix a colorless compound with a strong odor into some worm food, forming a short-term memory association in about one hour.

“Once they associate that odor with food they move toward that odor,” Mor said, adding that “that is how we give them the quiz.”

The research team also will explore how alpha-synuclein enters neurons in the gut. Recent cell-based studies suggested that toxic clumps bind to proteoglycans, a type of protein coated with sugar molecules, at the surface of cells, which help them get into cells.

We are modeling gut-to-brain alpha-synuclein transmission, which we believe is one potential way that this disease occurs in humans and now we will test cognitive function.

In earlier research, Mor showed that suppressing certain genes related to pathways that generate proteoglycans reduced the loss of dopamine-producing neurons and lessened some disease symptoms in the worms.

“We think we are blocking alpha-synuclein from actually getting into the cells,” Mor said.

To assess whether this is true, the team is inhibiting 17 genes related to proteoglycans that they suspect are involved in this process.

The large-scale screening of currently approved medicines will be focused on those that suppress alpha-synuclein’s toxicity that disrupts normal neuron metabolism and function, resulting in their death.

“Cellular metabolism is a key feature of how the neurons are dying,” Mor said.

This brain-gut connection in Parkinson’s is in line with the disease’s risk being influenced by both genetic and environmental factors. Such environmental factors may include exposure to harmful substances in food, water, or at home or work that may trigger alpha-synuclein misfolding in the gut.

“We should know if we are endangering ourselves and right now, we don’t know,” Mor added.

Mor’s mentors on the grant include Chandramohan Wakade, associate dean of research in the AU College of Allied Health Sciences, and Erhard Bieberich, PhD, a biochemist at the University of Kentucky College of Medicine.