The development and maintenance of polarity is paramount to neuronal development and function. The loss of this cell state is realized in many neurodegenerative diseases and ultimately leads to cell death. This project will lead to a greater understanding of the mechanisms responsible for polarization and its maintenance. The goal of this project is to characterize the contribution that the recently discovered LKB1 kinase pathway plays in axon growth and branching through polarized transport of cargo.
Specific Aim 1 will provide the necessary framework for understanding how LKB1 and NUAK1/2 affect the transport of mitochondria in the axon.
Specific Aim 2 will characterize the mechanism by which transport is regulated by determining the downstream components of the kinase pathway. The interaction between LKB1/NUAK and the mitochondrial anchor protein syntaphilin will be the main focus of this aim.
Specific Aim 3 will then attempt to link mitochondrial transport in the axon to proper axon branching and projection within layer 2/3 neurons of the cortex. This research will provide important new knowledge that will be useful in understanding the basic mechanisms at work in many neurodegenerative diseases including Alzheimer's, Huntington's and Parkinson's.
Neuron polarization is required for proper neuron function. Disruption of polarization and the mechanisms that underlie its maintenance are known to be major factors in many neurodegenerative diseases including ALS, Alzheimer's, Huntington's and Parkinson's.
|Kwon, Seok-Kyu; Sando 3rd, Richard; Lewis, Tommy L et al. (2016) LKB1 Regulates Mitochondria-Dependent Presynaptic Calcium Clearance and Neurotransmitter Release Properties at Excitatory Synapses along Cortical Axons. PLoS Biol 14:e1002516|
|Lewis Jr, Tommy L; Turi, Gergely F; Kwon, Seok-Kyu et al. (2016) Progressive Decrease of Mitochondrial Motility during Maturation of Cortical Axons InÂ Vitro and InÂ Vivo. Curr Biol 26:2602-2608|
|Ebrahimi-Fakhari, Darius; Saffari, Afshin; Wahlster, Lara et al. (2016) Impaired Mitochondrial Dynamics and Mitophagy in Neuronal Models of Tuberous Sclerosis Complex. Cell Rep 17:1053-1070|
|Courchet, Julien; Lewis Jr, Tommy L; Lee, Sohyon et al. (2013) Terminal axon branching is regulated by the LKB1-NUAK1 kinase pathway via presynaptic mitochondrial capture. Cell 153:1510-25|
|Lewis Jr, Tommy L; Courchet, Julien; Polleux, Franck (2013) Cell biology in neuroscience: Cellular and molecular mechanisms underlying axon formation, growth, and branching. J Cell Biol 202:837-48|
|Lewis Jr, Tommy L; Polleux, Franck (2012) Neuronal morphogenesis: Golgi outposts, acentrosomal microtubule nucleation, and dendritic branching. Neuron 76:862-4|
|Lewis Jr, Tommy L; Mao, Tianyi; Arnold, Don B (2011) A role for myosin VI in the localization of axonal proteins. PLoS Biol 9:e1001021|