Hereditary congenital defects that impair lysosomal degradation often affect the nervous system before other organs, suggesting an increased or specialized neuronal demand for lysosomal function. The objective of our work is to understand and manipulate lysosomal degradation in order to improve neuronal function by utilizing a Drosophila model for Charcot-Marie-Tooth type 2B (CMT 2B) disease. CMT 2B is an autosomal dominant sensory neuropathy caused by mutations in the late endosomal GTPase rab7. In a systematic characterization of all rab GTPases, we discovered that rab7 is expressed in neurons at elevated levels prior to other cell types. We have generated the first null mutants in rab7 in Drosophila;to our knowledge rab7 knock-outs in mouse or zebrafish have not been characterized. Loss of rab7 in Drosophila causes late developmental defects in neurons and postnatal progressive degeneration of sensory nerve terminals that can be rescued by neuron-specific rab7 cDNA expression. In further similarity to the human disease, rab7 mutant nerve terminals are characterized by endolysosomal degradation and protein accumulation defects. Overexpression of classical dominant negative (GDP-bound) or constitutively active (GTP-bound) Rab7 does not mimic the null mutant and disease phenotypes in vivo. Nonetheless, human CMT 2B mutations have been proposed to represent dominant gain-of-function alleles. In contrast, based on our preliminary data, we hypothesize that the human disease mutations are partial loss-of-function alleles that may cause a dominant phenotype through haploinsufficiency in heterozygous patients. We will genetically and mechanistically test this hypothesis in Drosophila. We will further elucidate the precise degradation defects associated with loss of rab7 in neuronal and non-neuronal cell types by analyzing the null mutant and known human disease mutations in Drosophila. We will thereby establish the first animal model for CMT 2B disease. In addition, we will utilize this model as a genetic inroad to study the cell biological mechanisms underlying the increased neuronal sensitivity to endolysosomal defects. Finally, we seek to establish methods to manipulate the degradative capacity of neurons affected by endolysosomal dysfunction.

Public Health Relevance

The proposed project has direct and substantial relevance for public health, because we present the first genetic model for the sensory neuropathy Charcot-Marie-Tooth type 2B disease. The experiments described in this grant are aimed at understanding the cell biological cause of pathology in this neuropathy as well as a class of related lysosomal dysfunction disorders and will have an impact on the choice of therapeutic approaches to developing potential treatment.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Synapses, Cytoskeleton and Trafficking Study Section (SYN)
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Neuhold, Lisa
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University of Texas Sw Medical Center Dallas
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