“A lot of ALS and neuromuscular disease research has attempted to identify that first domino, but we’re looking at the problem in a different way: What if there is no way to stop that first domino? Then you have to characterize the multiple and different pathologies that cumulatively lead to the disease,” Ottem explained.
That is exactly what Ottem and his team of students are doing. The group is entering the second year of a three-year study, “Investigating the Role of Muscle-Derived BDNF in Neuromuscular Disease Pathology,” funded by the National Institute for Neurological Disorders and Stroke, National Institute of Health (NIH). Ottem, principle investigator on the proposal, has chosen to focus on a single protein, brain-derived neurotrophic factor or BDNF, and its relationship to what is known as the “motor unit”: motoneurons and muscle that produce BDNF and work together in muscle movement. Their hypothesis, Ottem explained, is that the absence of BDNF is a major trigger in the development of muscle and motor neuron atrophy: “If you take away BDNF from the muscles, will the motor neurons get sick? We’ve found the answer is yes.”
The project, underway in Ottem’s laboratory on NMU’s campus, uses transgenic mice to test the results of deleting BDNF from muscle fibers, characterizing the neurotrophin’s absence on the health of both the muscles and motorneurons.
“If you take away this protein from muscles, the mice are born with no obvious pathology, but as they age the neurotrophin (BDNF) becomes necessary for maintaining the health of the motor unit. So essentially they experience a condition very similar to adult-onset ALS or similar neuromuscular diseases,” Ottem explained.
Ottem added the mice are “not as sick as genetic models of ALS,” which indicates a loss of BDNF from muscle may be one of a “set of pathologies” that leads to the disease: “We may have addressed one source,” he said. The key now, he added, is to determine at what age the loss of muscle BDNF triggers this pathology.
“If you can address the most profound pathology, it could be a promising treatment strategy. It could go a long way in improving the quality of life of patients,” he said.
While one profound goal of the project is to work toward such a possibility, it is not the only objective. The award was granted via the NIH’s R15 program, which supports research projects conducted by faculty and students at primarily undergraduate teaching institutions. Research I institutions are not eligible for the program, giving universities like NMU a shot at substantial pots of research funding. The aim, which Ottem strongly acknowledged, is also to offer students hands-on experience and training in biomedical and behavioral sciences. He said the point is best summed up by a comment from a panelist who reviewed his project’s proposal:
“Northern Michigan University is the epitome of what the R15 program hopes to accomplish. With over 70% of the student population being the first of their families to attend college and a high rate of success of graduates entering professional programs, the program has a solid track record of helping attract and train students to do research.”
The flux of students who have worked on the project so far have certainly reaped benefits. Students who worked in Ottem’s lab during the first year of the project have gone on to the likes of Michigan State School of Medicine (Courtney Johnston, Leah Heron and Olivia Juntila), Ohio College of Podiatric Medicine (Bradley Benson) and University of Tennessee Biochemistry and Cellular and Molecular Biology PhD Program (Kate Abrahamsson).
Current students in the lab are: Emily Pomeroy, Marc Madigan, Amanda Taisto, Rebecca Dangremond, Neil Poglese, Alexandra Cara, Luke Van Osdol, Rozemary Howard, Calvin Fries, Ryan Budin, Ryan Brandt and Jeff Van Raden. Ottem said the experience these students are gaining is invaluable.
“A graduate student presented at the Society for Neuroscience Annual Conference in New Orleans and in December, she will be presenting at the 23rd International Symposium on Amyotrophic Lateral Sclerosis and Motorneuron Diseases in Chicago,” he said. “The conference is extremely selective regarding the presentations it allows. This is huge for the student, and NMU.”