A research collaboration between three Montana State University faculty members recently received a grant to help fund their study on the connection between a rare genetic neurological disease and metabolism, the human gut microbiome and degeneration of the nervous system. The work could further the understanding of what causes more common neurodegenerative diseases and eventually pave the way for therapeutics to treat them.
The National Institutes of Health awarded $2.9 million to MSU professors Frances Lefcort, Seth Walk and Valerie Copié for their research into Familial dysautonomia, a disease that attacks and devastates the nervous system. The five-year grant will fund their research and student education, including the several undergraduates and two graduate students who are currently contributing research to the project.
Lefcort's lab has researched Familial dysautonomia, a disease that runs in her family, for eight years. She explained that the disease begins in utero, where parts of the nervous system don't develop properly. It grows progressively worse over the years as nerve cells die.
While rare, the genetic mutation that causes Familial dysautonomia has been identified, which makes it a useful model for research into other neurodegenerative diseases, such as Alzheimer's and Parkinson's, said Lefcort, who is the Letters and Science Distinguished Professor in MSU's Department of Cell Biology and Neuroscience.
She said one common problem among people with Familial dysautonomia is that they are very thin and have trouble putting on weight, which would suggest a metabolic problem. Another is that the gastrointestinal tract doesn't function normally, which leads to diarrhea, constipation, esophageal reflux or other gastrointestinal issues.
Lefcort sought out experts in both of those research areas from among her MSU colleagues: Walk's expertise is in gut microbiomes, and Copié studies metabolism. She learned that the nervous system is closely involved with the human gut microbiome and is affected by metabolism.
"There are more than 100 million neurons just in your gut, and it's well known that there's extensive communication between the brain and the gut through the gut-brain axis," Lefcort said.
Realizing the likely connection between their research, the interdisciplinary trio collaborated to further study the roles of the gut microbiome, nervous system and metabolism (also called "metabolome") in Familial dysautonomia. Using Walk's specially bred, germ-free laboratory mice as models, the scientists hope to selectively manipulate "each leg of the triangle to determine how these systems affect each other and contribute to neurodegenerative disease," Lefcort said.
"Nothing like this has ever been done in this disease, and it's only starting to be done in major disease like Alzheimer's and Parkinson's," Lefcort said. "We feel that work from this grant will not only inform our understanding of Familial dysautonomia, but also provide a great model for understanding how the gut microbiome, metabolome and nervous system are interacting in these major neurogenerative diseases."
The trio has already gathered promising preliminary data through a collaboration with New York University's Dysautonomia Center, which sees all North American patients with Familial dysautonomia.
"They have sent us stool and blood samples from their patients and their patients' relatives, and we've already shown that the microbiome of those patients is significantly different from that of their relatives," Lefcort said. "We have good data suggesting we have something here, and now using our mouse models, we can really tease apart the causality -- is there a metabolic problem that's affecting the microbiome, and/or is it the microbiome that's altering metabolism and contributing to the neurodegeneration?"
Lefcort will analyze the nervous system in the gastrointestinal tracts of the laboratory mice, seeking answers to questions such as whether altering the metabolism or microbiome helps prevent neurodegeneration.
Walk will direct the microbiome-focused aspects of the project, which will include a detailed investigation of bacteria living in the intestines of patients who have neurodegenerative disease. He will also lead research focused on the microbiome and whether bacteria in the gut produce compounds that trigger neurons to grow or to die. He'll do this using cutting-edge DNA sequencing coupled with germ-free and gnotobiotic mice.
"Germ-free mice are completely sterile and do not have any microorganisms living inside them or on them. These animals help us understand what aspects of our 'health' are missing when microbes are not around," said Walk, an associate professor in MSU's Department of Microbiology and Immunology in the College of Agriculture and the College of Letters and Science. "Gnotobiotic mice have a defined microbiome, whereby we can discover the specific benefits of a particular microbial community."
Copié, a professor in MSU's Department of Chemistry and Biochemistry and director of the Nuclear Magnetic Resonance Center, will lead the effort to identify the metabolic processes that are impaired by Familial dysautonomia and how those impairments in energy production affect the gut-brain axis and contribute to neurodegeneration.
"Our lab will be responsible for undertaking the global profiling and characterization of small molecule metabolites present in stool and serum samples of Familial dysautonomia patients and animal models," Copié said. "These studies will integrate nuclear magnetic spectroscopy and mass spectrometry techniques to identify the metabolic changes that take place in Familial dysautonomia. Our goal is to explore whether we can redress the metabolic deficits observed in Familial dysautonomia via microbiome intervention and whether restoring healthy metabolomes can help or either slow down neurodegeneration or help restore neuronal health."
The high-resolution metabolic data generated by the NMR Center will contribute to the field of biomedical research and "will help us better understand how the metabolome, microbiome and neuronal circuitry interact together and can lead to irreversible neurodegeneration when impaired," Copié said.
"It's clear that the triggers are different for Parkinson's, Alzheimer's and ALS, but they all converge on common downstream pathways," Lefcort said. "We have shown that Familial dysautonomia converges on the same pathways. Now, we're trying to find out if we can intervene at these common points.
"Whatever we discover here is going to be applicable to the major neurodegenerative disorders," she said.