“Regulation of Axon Degeneration after Injury and in Development by the Endogenous Calpain Inhibitor Calpastatin” Yang J, et al.;
Neuron, 2013 80:1175-1189
Submitted by Zaeem Siddiqi, MD, PhD
About the Study
Following injury to an axon, the segment distal to the lesion site undergoes Wallerian degeneration characterized by loss of the action potential, destruction of the cytoskeleton, membrane fragmentation, and demyelination. Axonal degeneration also occurs during neurodegenerative disorders as well as during the course of normal process of development as the neurons and their connections undergo maturation through pruning. The molecular pathways regulating these processes remain incompletely understood. Calpains are Ca2+-activated proteases whose activation can result in proteolysis of vital cellular components, including axons. Calpain activity is critically controlled by proteinaceous inhibitor calpastatin, which binds and inhibits calpains when the protease is activated by Ca2+ influx.
Yang, et al., studied the role of calpastatin in axonal degeneration after injury in neuronal cultures where the cell bodies had been separated from the axons. Calpastatin depletion was observed in degenerating axons after physical injury, and maintaining calpastatin inhibited degeneration of transected axons in vitro and in the optic nerve in vivo. Calpastatin depletion also occurred in a caspase-dependent manner in trophic factor-deprived sensory axons of the dorsal root ganglion and was required for this in vitro model of developmental degeneration. In vivo, calpastatin regulated the normal pruning of retinal ganglion cell axons. The authors conclude that calpastatin may function as a key endogenous regulator of axon degeneration during normal development as well as after pathologic processes.
Axonal degeneration occurs within 24 to 36 hours after axonotmesis and the subsequent dying process of the distal stump has been well characterized. Mechanisms that may delay these processes can have considerable therapeutic potential and may provide a time window to reestablish continuity among the axons after the nerve trunk is injured. Calpain/calpastatin system is known to play an important role in cellular processes that involve membrane fusion events, such as neural vesicle exocytosis, and platelet and red-cell aggregation. How these processes delay the axonal degeneration remains intriguing and needs to be further elucidated.
About the News Science Editorial Board
The board helps to highlight significant, timely science news items for AANEM members. It reviews articles in journals and websites, identifies newsworthy items in the field each month, and writes article summaries.
Board members: Zaeem Siddiqi, MD, PhD (chair); Shan (Sarah) Chen, MD, PhD; Brent Goodman, MD; Ileana Howard, MD; Nicholas Johnson, MD; Carlos Luciano, MD; Andrew Tarulli, MD; Leigh Maria Ramos-Platt, MD