Endolysosomal Function in Neuronal Maintenance

Ut Southwestern Medical Center, Dallas TX

Investigators

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Abstract

DESCRIPTION (provided by applicant): Many defects in lysosomal degradation affect the nervous system before other organs, suggesting an increased or specialized neuronal demand for endomembrane degradation. I have generated the first null mutant for the ubiquitous endolysosomal rab GTPase rab7 in Drosophila. Partial or complete loss of rab7 causes neuropathy-like phenotypes in sensory neurons before other cell types. Moreover, four point mutations in human rab7 cause the autosomal dominant sensory neuropathy Charcot-Marie-Tooth type 2B (CMT 2B) through a partial loss-of-function mechanism. Both the Drosophila rab7 null mutant and the CMT 2B disease in human highlight the neuronal sensitivity to defects in endolysosomal degradative capacity. Based on my preliminary findings, I hypothesize that neurons have a specialized or increased requirement for endolysosomal degradation. I will test this hypothesis by combining fly genetics and novel live imaging approaches to quantitatively measure cargo-specificity and dynamics of rab7-dependent degradation at neuronal synapses compared to cell bodies and other cell types. Next, I will use genetic interaction experiments combined with imaging and electrophysiological read-outs to investigate the cellular mechanism of rab7 function in the context of ubiquitous autophagy and neuron-specific endolysosomal degradation mechanism. Finally, together with my Co-Sponsor, I will characterize rab7 function in mouse neuronal culture to test the generality of my findings from the Drosophila model. Together, my findings will elucidate the cellular mechanism of rab7-dependent degradation and its role in neuronal maintenance and longevity, with a potential therapeutic application in the establishment of methods to manipulate the degradative capacity of neurons affected by endolysosomal dysfunction.