Molecular Mechanism of Imac-dependent axonal transport

Boston Children'S Hospital, Boston MA

Investigators

Abstract

DESCRIPTION (provided by applicant): The proper function of complex neural networks relies on the development and stabilization of specific synaptic connections. In both developmental and neurodegenerative disorders disruption of proper synaptic structure and function plays a central role in the pathology of the disease. Due to the specialized morphology of neurons, active transport of proteins and organelles along cytoskeletal filaments has proven to be critical not only for cell survival, axon outgrowth but also synaptogenesis. Moreover, the kinesin superfamily of molecular motors has been implicated the neurodegenerative disorders: Amyotrophic Lateral Sclerosis, Huntington disease and Parkinson's disease. In Drosophila melangastor, our lab identified the kinesin-3 family member, Imac, to be an essential motor for synaptogenesis. In imac null mutants, axons reach their proper targets but fail to form boutons, have decreased active zones and lack synaptic vesicles at the terminals. Imac is ubiquitously expressed throughout the nervous system and throughout the life of the animal suggesting a continued role for the transport of synaptic cargo after the initial stage of synaptic maturation i the embryo. Using Drosophila genetics, this proposal aims to characterize the function of Imac-dependent transport for synapse addition during larval development, to determine if active transport of synaptic cargo is required synapse maintenance. Additionally, we will perform structure function analysis and biochemistry to identify proteins that associate with Imac to regulate trafficking and facilitate cargo binding. Our long-term goal is to further our understanding of the molecular mechanisms that regulate synapse development and maintenance. PUBLIC HEALTH RELEVANCE: This project will further characterize the role of a protein that we found to be essential for axonal transport during synaptic development. In neurons, proteins produced in the cell body need to be transported down the axons for the proper assembly of synaptic connections in the nervous system. Disruption of proper synapse formation and maintenance can lead to many forms of developmental and neurodegenerative disorders.