Regulation of axon degeneration after injury and in development by the endogenous calpain inhibitor calpastatin

Jing Yang; Robby M Weimer; Dara Kallop; Olav Olsen; Zhuhao Wu; Nicolas Renier; Kunihiro Uryu; Marc Tessier-Lavigne

doi:10.1016/j.neuron.2013.08.034

Regulation of axon degeneration after injury and in development by the endogenous calpain inhibitor calpastatin

Neuron. 2013 Dec 4;80(5):1175-89. doi: 10.1016/j.neuron.2013.08.034. Epub 2013 Nov 7.

Authors

Jing Yang¹, Robby M Weimer, Dara Kallop, Olav Olsen, Zhuhao Wu, Nicolas Renier, Kunihiro Uryu, Marc Tessier-Lavigne

Affiliation

¹ Laboratory of Brain Development and Repair, The Rockefeller University, New York, NY 10065, USA; Research and Early Development, Genentech Inc., South San Francisco, CA 94080, USA.

PMID: 24210906
DOI: 10.1016/j.neuron.2013.08.034

Abstract

Axon degeneration is widespread both in neurodegenerative disease and in normal neural development, but the molecular pathways regulating these degenerative processes and the extent to which they are distinct or overlapping remain incompletely understood. We report that calpastatin, an inhibitor of calcium-activated proteases of the calpain family, functions as a key endogenous regulator of axon degeneration. 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 and was required for this in vitro model of developmental degeneration. In vivo, calpastatin regulated the normal pruning of retinal ganglion cell axons in their target field. These findings identify calpastatin as a key checkpoint for axonal survival after injury and during development, and demonstrate downstream convergence of these distinct pathways of axon degeneration.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Animals, Newborn
Armadillo Domain Proteins / genetics
Armadillo Domain Proteins / metabolism
Axotomy
Brain / cytology
Calcium-Binding Proteins / genetics
Calcium-Binding Proteins / metabolism*
Calpain / metabolism
Cell Survival / genetics
Cells, Cultured
Cytoskeletal Proteins / genetics
Cytoskeletal Proteins / metabolism
Disease Models, Animal
Embryo, Mammalian
Enzyme Inhibitors / pharmacology
Ganglia, Spinal / cytology
Ganglia, Spinal / ultrastructure
Gene Expression Regulation / physiology*
Green Fluorescent Proteins / genetics
Green Fluorescent Proteins / metabolism
HEK293 Cells
Humans
In Vitro Techniques
Mice
Microscopy, Electron, Transmission
Nerve Degeneration / etiology*
Nerve Degeneration / metabolism*
Nerve Growth Factor / metabolism
Nerve Tissue Proteins / metabolism
Neurons / pathology
Neurons / ultrastructure
Nicotinamide-Nucleotide Adenylyltransferase / genetics
Nicotinamide-Nucleotide Adenylyltransferase / metabolism
RNA, Messenger / metabolism
RNA, Small Interfering / metabolism
Sciatic Neuropathy / complications
Sciatic Neuropathy / metabolism*
Time Factors
Transduction, Genetic
Wallerian Degeneration / pathology
Wallerian Degeneration / physiopathology*

Substances

Armadillo Domain Proteins
Calcium-Binding Proteins
Cytoskeletal Proteins
Enzyme Inhibitors
Nerve Tissue Proteins
RNA, Messenger
RNA, Small Interfering
SARM1 protein, mouse
Green Fluorescent Proteins
calpastatin
Nerve Growth Factor
Nmnat protein, mouse
Nicotinamide-Nucleotide Adenylyltransferase
Calpain