Date of Award
Master of Science
Brain-derived neurotrophic factor (BDNF) is a small, diffusible protein essential for the development and function of neurons. It is synthesized by many types of tissue, including muscle. BDNF actions are mediated via binding to its receptor, tyrosine receptor kinase B (TrkB). The BDNF-TrkB complex is endocytosed into a specialized vesicle, which induces downstream signaling cascades locally in the dendrites, or, more often, is delivered to the cell soma via retrograde axonal transport, where it modulates gene expression. BDNF activation of TrkB is critical for the initiation of axonal transport, and this cellular process relies on the interaction of numerous adaptor proteins, including dynactin and JIP3, which help bind cargo to motor proteins. Disruption of retrograde transport is a hallmark of several neuromuscular diseases, including SBMA, Huntington’s disease, and ALS. The roles of BDNF and TrkB are not well-characterized in muscle or motor neurons. This study addressed the function of TrkB in neuromuscular junctions (NMJs) and its roles in motor neuron axonal transport. The expression of TrkB, and its activated form, phosphorylated-TrkB (p-TrkB), were assessed in the presynaptic and postsynaptic terminals of gastrocnemius-associated NMJs of mice missing muscle-derived BDNF. Further, the accumulation of TrkB, p-TrkB, dynactin, and JIP3 were evaluated following sciatic nerve ligations to assess the functionality of axonal transport mechanisms in mice lacking muscle-synthesized BDNF. Pre- and postsynaptic TrkB activation was significantly reduced, and both anterograde and retrograde transport were significantly impaired in MuscleBDNF-deficient mice. This study provided insight into the disease process of neuromuscular diseases such as ALS.
VanOsdol, Luke A., "CHARACTERIZATION OF THE ROLES OF MUSCLE-SYNTHESIZED BRAIN-DERIVED NEUROTROPHIC FACTOR AND PRESYNAPTIC TYROSINE RECEPTOR KINASE B IN MOTOR NEURON AXONAL TRANSPORT" (2018). All NMU Master's Theses. 543.
Cellular and Molecular Physiology Commons, Disease Modeling Commons, Molecular and Cellular Neuroscience Commons, Molecular Biology Commons, Nervous System Diseases Commons, Other Genetics and Genomics Commons, Other Neuroscience and Neurobiology Commons