Disruption of the axon initial segment cytoskeleton is a new mechanism for neuronal injury. The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] Journal article

Title	Disruption of the axon initial segment cytoskeleton is a new mechanism for neuronal injury.
Author(s)	Schafer DP, Jha S, Liu F, Akella T, McCullough LD, Rasband MN
Institution	Department of Neuroscience, University of Connecticut Health Center, Farmington, Connecticut 06032, USA.
Source	J Neurosci 2009 Oct 21; 29(42):13242-54.
MeSH	Analysis of Variance Animals Anoxia Axons Calcium-Binding Proteins Calpain Cell Adhesion Molecules Cell Death Cells, Cultured Cerebral Cortex Cysteine Proteinase Inhibitors Cytoskeleton Disease Models, Animal Embryo, Mammalian Glucose Green Fluorescent Proteins Infarction, Middle Cerebral Artery Mice Mice, Inbred C57BL Nerve Growth Factors Nerve Tissue Proteins Neurons Neuroprotective Agents Rats Rats, Sprague-Dawley Transfection
Abstract	Many factors contribute to nervous system dysfunction and failure to regenerate after injury or disease. Here, we describe a previously unrecognized mechanism for nervous system injury. We show that neuronal injury causes rapid, irreversible, and preferential proteolysis of the axon initial segment (AIS) cytoskeleton independently of cell death or axon degeneration, leading to loss of both ion channel clusters and neuronal polarity. Furthermore, we show this is caused by proteolysis of the AIS cytoskeletal proteins ankyrinG and betaIV spectrin by the calcium-dependent cysteine protease calpain. Importantly, calpain inhibition is sufficient to preserve the molecular organization of the AIS both in vitro and in vivo. We conclude that loss of AIS ion channel clusters and neuronal polarity are important contributors to neuronal dysfunction after injury, and that strategies to facilitate recovery must preserve or repair the AIS cytoskeleton.
Language	eng
Pub Type(s)	Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S.
PubMed ID	19846712

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