Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease of motor neurons without a known cause or effective treatment. Our poor understanding of ALS pathogenesis is partly due to a lack of simple animal models of motor neuron degeneration. The candidate, Thomas Lloyd M.D., Ph.D. proposes to characterize and utilize a novel model of motor neuron disease using the powerful genetic organism Drosophila melanogaster. Emerging data suggest that defects in axonal transport or other vesicle trafficking events may be a primary cause of this disease. To investigate the role of vesicle transport in motor neuron disease, we have introduced a mutation in the P150 subunit of dynactin into Drosophila that is present in a rare familial form of ALS. Flies expressing mutant P150 have several phenotypes reminiscent of ALS including aggregates of mutant protein, defects in axonal transport, and adult-onset, progressive paralysis and early death. The goal of this proposal is to further characterize this simple genetic model of motor neuron disease, and then to use it to screen for genetic suppressors of motor neuron degeneration.
Aim 1 will investigate the effects of disease-associated P150 mutations on vesicle transport in Drosophila in vitro and in vivo to test the hypothesis that these mutations disrupt specific vesicle transport processes.
Aim 2 will test the hypothesis that disease-associated P150 mutations cause motor neuron and neuromuscular junction pathology resembling that seen in ALS patients.
Aim 3 will first characterize the effect of an identified suppressor of mutant P150 on these motor neuron phenotypes. We will then screen the Drosophila genome for additional genetic modifiers of mutant P150 in hopes of identifying novel genes critical to disease pathogenesis, a powerful approach not feasible in mouse models. Identified genetic interactors are potential drug targets, so a future direction of this proposal is to validate identified interacting genes in mouse models of ALS. The studies proposed will be carried out in the laboratory of Alex Kolodkin, an expert in motor neuron connectivity in Drosophila and mice, with mentorship from Jeff Rothstein, director of the Robert Packard Center for ALS Research. The neuroscience and neurology departments at Johns Hopkins provide an exceptional environment for the development of academic neurologists. The training and mentorship provided by this grant will give Dr. Lloyd the expertise and tools needed to become a successful, independent physician-scientist who will devote his career to identifying new treatments for ALS.
The development of treatments for ALS is hindered by the lack of simple animal models of this disease. This proposal will characterize a new fruitfly model of ALS to help understand the genetic causes of ALS and to help find new drugs targets for this devastating disease.
|Chung, Tae; Prasad, Kalpana; Lloyd, Thomas E (2014) Peripheral neuropathy: clinical and electrophysiological considerations. Neuroimaging Clin N Am 24:49-65|
|Machamer, James B; Collins, Sarah E; Lloyd, Thomas E (2014) The ALS gene FUS regulates synaptic transmission at the Drosophila neuromuscular junction. Hum Mol Genet 23:3810-22|
|Lloyd, Thomas E; Machamer, James; O'Hara, Kathleen et al. (2012) The p150(Glued) CAP-Gly domain regulates initiation of retrograde transport at synaptic termini. Neuron 74:344-60|
|Lloyd, Thomas E (2010) Novel therapeutic approaches for inclusion body myositis. Curr Opin Rheumatol 22:658-64|
|Lloyd, Thomas E; Taylor, J Paul (2010) Flightless flies: Drosophila models of neuromuscular disease. Ann N Y Acad Sci 1184:e1-20|