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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32NS080464-01
Application #
8397082
Study Section
Special Emphasis Panel (ZRG1-F03A-N (20))
Program Officer
Riddle, Robert D
Project Start
2012-07-01
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$49,214
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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 In Vitro and In 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