Deciphering How the Gut May Play a Role in Disease Development and Progression
When life gets confusing or difficult, a common piece of advice is to stop and ask: “What is your gut telling you?” For Benjamin Dehay, PhD, recipient of a Parkinson’s Foundation Impact Award, the phrase is literal: he and his research team (Dr. Ariadna Laguna Tuset from Barcelona and Dr. Laura Parkkinen from Oxford) study how the gastrointestinal tract (the gut) may play a role in the development and progression of Parkinson’s disease (PD).
A major hallmark of PD is the misfolding (or clumping) of a brain protein called alpha-synuclein found inside neurons. These clumps often spread from cell to cell, eventually causing cell death and, ultimately, contributing to the progression of the disease. As neurodegeneration spreads in the brain, it leads to noticeable and eventually worsening symptoms.
Recent research has shown that alpha-synuclein, previously only observed in the brain, can also be found in the enteric nervous system, which monitors and manages gastrointestinal function. Not only might this explain why people with PD experience gut-related symptoms like constipation, but it may also reveal a new origin point for the disease.
Animal studies have shown that alpha-synuclein might travel between the gut and brain along the vagus nerve — which connects the brain to the gut — suggesting that initial alpha-synuclein clumps could potentially originate in the gut before spreading to the central nervous system.
Dr. Dehay and his team at the Institute of Neurodegenerative Diseases in Bordeaux, France, and his collaborators will investigate how misfolded alpha-synuclein proteins in the gastrointestinal tract may differ from the ones found in the brain and whether such differences affect disease progression.
First, Dr. Dehay will extract alpha-synuclein clumps from post-mortem brain and colon (part of the gut) tissue samples of people with Parkinson’s. He will compare their size, shape, and ability to form larger, more disruptive clumps.
Next, we will inject gut-derived alpha-synuclein into the brains of one group of aged mice and brain-derived alpha-synuclein into the guts of another group of aged mice and monitor the mice’s behavioral and biochemical health. This comparison will allow Dr. Dehay to measure differences in disease progression, depending on which direction alpha-synuclein clumps travel along the gut-brain axis.
Speaking on the impact of his research with this Parkinson’s Foundation support, Dr. Dehay said, “Thanks to this award, our ultimate ambition, using state-of-the-art technologies, unique human samples, and experimental expertise, is to provide direct evidence of how gastrointestinal tract- versus brain-derived alpha-synuclein aggregates spread and become toxic in mice along the brain-gut axis.”
By investigating the various structures and biochemical properties of the hallmark protein in PD in different regions, we can enhance our understanding of the disease, create new treatments and diagnostic tools, and ultimately improve outcomes for people with Parkinson’s.
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