LKB1 function in axon development through regulation of mitochondrial trafficking

描述(由申请人提供)：极性的发展和维持对神经元的发育和功能至关重要。这种细胞状态的丧失在许多神经退行性疾病中都会发生，并最终导致细胞死亡。该项目将使人们更好地了解两极分化及其维持的机制。这个项目的目标是表征最近发现的LKB1激酶通路在轴突生长和通过极化的货物运输分支中所起的作用。具体目标1将为理解LKB1和NUAK1/2如何影响轴突中线粒体的运输提供必要的框架。具体目标2将通过确定激酶途径的下游成分来描述运输被调控的机制。LKB1/NUAK与线粒体锚定蛋白Synaphlin之间的相互作用将是这一目标的主要焦点。然后，特殊目标3将尝试将轴突中的线粒体运输与适当的轴突分支和皮质第2/3层神经元内的投射联系起来。这项研究将提供重要的新知识，有助于理解许多神经退行性疾病的基本机制，包括阿尔茨海默氏症、亨廷顿氏症和帕金森氏症。

DESCRIPTION (provided by applicant): 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.