title: Caspase-2 is upregulated after sciatic nerve transection and its inhibition protects dorsal root ganglion neurons from apoptosis after serum withdrawal.
abstract: Sciatic nerve (SN) transection-induced apoptosis of dorsal root ganglion neurons (DRGN) is one factor determining the efficacy of peripheral axonal regeneration and the return of sensation. Here, we tested the hypothesis that caspase-2 (CASP2) orchestrates apoptosis of axotomised DRGN both in vivo and in vitro by disrupting the local neurotrophic supply to DRGN. We observed significantly elevated levels of cleaved CASP2 (C-CASP2), compared to cleaved caspase-3 (C-CASP3), within TUNEL+DRGN and DRG glia (satellite and Schwann cells) after SN transection. A serum withdrawal cell culture model, which induced 40% apoptotic death in DRGN and 60% in glia, was used to model DRGN loss after neurotrophic factor withdrawal. Elevated C-CASP2 and TUNEL were observed in both DRGN and DRG glia, with C-CASP2 localisation shifting from the cytosol to the nucleus, a required step for induction of direct CASP2-mediated apoptosis. Furthermore, siRNA-mediated downregulation of CASP2 protected 50% of DRGN from apoptosis after serum withdrawal, while downregulation of CASP3 had no effect on DRGN or DRG glia survival. We conclude that CASP2 orchestrates the death of SN-axotomised DRGN directly and also indirectly through loss of DRG glia and their local neurotrophic factor support. Accordingly, inhibiting CASP2 expression is a potential therapy for improving both the SN regeneration response and peripheral sensory recovery.
authors: Neurotrauma and Neurodegeneration Section, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, United Kingdom.
authors: Vasanthy
authors: V
authors: Vigneswara
authors: Martin
authors: M
authors: Berry
authors: Ann
authors: A
authors: Logan
authors: Zubair
authors: Z
authors: Ahmed
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053143:Caspase 2 / Q000235:genetics* / Q000378:metabolism*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D061945:Caspase Inhibitors / Q000494:pharmacology; D002467:Cell Nucleus / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D003600:Cytosol / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology / Q000201:enzymology* / Q000601:surgery; D020287:In Situ Nick-End Labeling / Q000379:methods; D009416:Nerve Regeneration / Q000235:genetics / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D009475:Neurons, Afferent / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012583:Schwann Cells / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D012584:Sciatic Nerve / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D061945:Caspase Inhibitors; D053143:Caspase 2; D053148:Caspase 3