Disruption of the axon initial segment cytoskeleton is a new mechanism for neuronal injury.
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.
Schafer
Dorothy P
DP
Department of Neuroscience, University of Connecticut Health Center, Farmington, Connecticut 06032, USA.
Jha
Smita
S
Liu
Fudong
F
Akella
Trupti
T
McCullough
Louise D
LD
Rasband
Matthew N
MN
D000704:Analysis of Variance; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002154:Calpain / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003599:Cytoskeleton / Q000187:drug effects / Q000473:pathology*; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005947:Glucose / Q000172:deficiency; D049452:Green Fluorescent Proteins / Q000235:genetics; D000860:Hypoxia / Q000473:pathology; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009414:Nerve Growth Factors / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection / Q000379:methods
D002135:Calcium-Binding Proteins; D015815:Cell Adhesion Molecules; D015853:Cysteine Proteinase Inhibitors; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; C504593:Nfasc protein, mouse; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; C033668:calpastatin; D002154:Calpain; D005947:Glucose