$8.9M Grant Will Drive Research Into Gut-to-brain Protein Spread

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by Yedida Y Bogachkov PhD |

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A neurological surgery professor from Weill Cornell Medicine and his team will use a three-year, $8.9 million research grant to investigate how abnormal protein clumps in the gut can spread to the brain and help drive the early stages of Parkinson’s disease.

This grant, from the Aligning Science Across Parkinson’s initiative, called ASAP, will further research suggesting that these protein clumps, or aggregates, initially form in the nerve cells in the intestines and “trigger the classic signs of Parkinson’s only after they travel to the brain, via a large gut-to-brain nerve called the vagus nerve,” the scientists said in a Weill Cornell Medicine press release.

Michael Kaplitt, MD, PhD, also a neurosurgeon at New York-Presbyterian/Weill Cornell Medical Center, and an expert in developing surgical therapies for movement disorders, will be leading the multi-institutional research team funded by the grant.

“Interaction between the body and the brain is a very exciting and important area of research, and it is increasingly clear that, at least in some cases, Parkinson’s disease may begin in the gut, with the disease spreading through nerve connections to the brain and eventually throughout the brain,” Kaplitt said.

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The Michael J. Fox Foundation for Parkinson’s Research is ASAP’s partner in implementing this grant. ASAP’s goal is to advance research for Parkinson’s through collaborative efforts, research-enabling resources, and data sharing.

“I am so grateful to ASAP and the Michael J. Fox Foundation for this exciting opportunity,” Kaplitt said, adding that the team seeks “to not only understand how this gut-to-brain transmission happens, but [to] also potentially intervene genetically to improve brain function and stop the spread of disease.”

Protein clumps, comprised of fiber-like aggregates of the protein alpha-synuclein, are often seen as the drivers of disease progression in Parkinson’s. These synuclein fibrils, or small fibers, tend to extend throughout the brain in a characteristic pattern throughout the disease course.

Kaplitt and his collaborators will use a recently developed mouse model of the gut-to-brain disease process to explore exactly how Parkinson’s may begin in the intestines. The team also will investigate how this concept may relate to earlier, “pre-motor” signs of the disease such as sleep disturbances.

Key to the research will be examining whether this process differs between men — males are known to be more affected by the disease — and pre-menopausal women.

The scientists hope to be able to develop methods for detecting gut alpha-synuclein aggregates, and to prevent their migration to the brain.

For the project, Kaplitt will collaborate with investigators Ted Dawson, MD, PhD, director of the Johns Hopkins Institute for Cell Engineering, in Maryland, and a professor of neurology at the university’s School of Medicine, and Per Svenningsson, MD, PhD, of the Karolinska University Hospital, in Sweden, and a professor of neurology at the Karolinska Institutet.

“There is a growing amount of evidence of the gut’s role in Parkinson’s disease, and we are developing excellent scientific models to study the disease’s progression from the start,” Dawson said.

“Our multidisciplinary approach holds tremendous promise in identifying innovative ways to treat Parkinson’s disease,” he added.

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Roberta Marongiu, PhD, a project co-investigator and assistant professor at the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine, will conduct the research examining the effects of menopause on Parkinson’s.

“My group will study how sex and menopause influence the spread of Parkinson’s disease pathology from the gut to the brain in the early stages of the disease,” Marongiu said.

“This will help us understand more about the intricate relationship between hormones and onset of Parkinson’s and has the potential to identify novel precision medicine approaches for men and women,” she said.

The team also includes several other researchers with differing specialties. Some of the scientists will focus on the imaging of vagus-linked gut neurons to track the spread and effects of early stages of synuclein aggregation, while others are investigating whether microglia — immune cells in the brain — can be responsible for some of the patterns of spread once the synuclein clumps from the intestines enter the brain.

“Bringing together this international team of the most forward-thinking, most innovative researchers in Parkinson’s disease holds so much promise for patients,” said Philip E. Stieg, MD, PhD, chair of neurological surgery at Weill Cornell Medicine.

“We all look forward to the discoveries that come from this research, which has the potential to create effective new treatments for this debilitating disease,” he said.

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