Mechanisms of Motor Neuron Injury in Acute Flaccid Myelitis

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Project Summary/Abstract Mechanisms of Motor Neuron Injury in Acute Flaccid Myelitis Acute flaccid myelitis (AFM) is an infectious disorder of motor neurons that resembles poliomyelitis. AFM predominantly affects children and has tragic consequences, often leading to lifelong paralysis. Concerningly, the incidence of AFM has increased exponentially with each recent outbreak. Effective treatment options for AFM are lacking, owing primarily to our poor understanding of disease pathogenesis. In the proposed work, I will investigate mechanisms of motor neuron toxicity in AFM. The majority of cases of AFM are caused by Enterovirus D68 (EV68). Therefore, I will focus on the infection of motor neurons by EV68 as a model of AFM. First, I will evaluate the role of nucleocytoplasmic transport in motor neuron toxicity following EV68 infection. This pathway is known to be altered in enterovirus infection and is also a key determinant of motor neuron toxicity in neurodegenerative disease. I will further define the mechanism of disruption of the nuclear pore complex by EV68, its effects on nucleocytoplasmic transport and motor neuron toxicity, and whether it can be pharmacologically targeted to prevent motor neuron death in vitro. Second, to better define the pathologic cascade following EV68 infection, I will investigate early pathologic events in a novel co-culture system including motor neurons and muscle fibers. I will specifically investigate changes in motor neuron morphology, electrophysiologic activity, and neuromuscular junction integrity. Third, I will determine whether host genetic background influences EV68 infectivity or subsequent motor neuron toxicity by studying iPS motor neurons derived from AFM patients compared to unrelated controls. Collectively, these studies will advance our understanding of pathogenic mechanisms in EV68-associated AFM and evaluate putative therapeutic targets. The experiments will also develop and refine model systems for the study of AFM and generate important preliminary data for future studies leading to scientific independence. The training plan will provide new training in virology methods and extend my expertise in iPS-based neurologic disease modeling and advanced microscopy.