Michael Francis, PhD
Faculty page: http://www.umassmed.edu/faculty/show.cfm?faculty=1183
Lab website: http://www.mfrancislab.org/
Ion channel mediated neurodegeneration
Roles for ionotropic receptor mediated signaling in the nervous system extend far beyond a well-characterized participation in cell-cell communication at synapses. Ionotropic receptor activation is one of several key factors that influences cell survival in developing and mature nervous systems. Work in our laboratory has shown that hyperactivation of nicotinic acetylcholine receptors (nAChR) located on excitatory motor neurons leads to motor neuron degeneration in the nematode Caenorhabditis elegans. We have found that C. elegans double mutants lacking two genes previously implicated in calcium homeostasis and necrotic cell death (crt-1/Calreticulin and cnx-1/Calnexin) are resistant to nAChR mediated toxicity and possess normal numbers of motor neuron cell bodies. Interestingly, under conditions in which death of the cell bodies was attenuated, we noted nAChR hyperactivation led to progressive destabilization of the motor neuron processes and, ultimately, paralysis in these animals. Our work to date suggests that ion channel hyperactivation has distinct consequences for neuronal cell bodies and processes. We are now working to uncover the molecular pathways that underlie ion channel mediated toxicity in both neuronal cell bodies and processes.
Barbagallo B, Prescott, HA, Boyle P, Climer J, Francis MM (2010). A dominant mutation in a neuronal acetylcholine receptor subunit leads to motor neuron degeneration in C. elegans. Journal of Neuroscience 30(42): 13932-13942.