title: Calpain-1 and calpain-2 play opposite roles in retinal ganglion cell degeneration induced by retinal ischemia/reperfusion injury.
abstract: Calpain has been shown to be involved in neurodegeneration, and in particular in retinal ganglion cell (RGC) death resulting from increased intraocular pressure (IOP) and ischemia. However, the specific roles of the two major calpain isoforms, calpain-1 and calpain-2, in RGC death have not been investigated. Here, we show that calpain-1 and calpain-2 were sequentially activated in RGC dendrites after acute IOP elevation. By combining the use of a selective calpain-2 inhibitor (C2I) and calpain-1 KO mice, we demonstrated that calpain-1 activity supported survival, while calpain-2 activity promoted cell death of RGCs after IOP elevation. Calpain-1 activation cleaved PH domain and leucine-rich repeat protein phosphatase 1 (PHLPP1) and activated the Akt pro-survival pathway, while calpain-2 activation cleaved striatal-enriched protein tyrosine phosphatase (STEP) and activated STEP-mediated pro-death pathway in RGCs after IOP elevation. Systemic or intravitreal C2I injection to wild-type mice 2h after IOP elevation promoted RGC survival and improved visual function. Our data indicate that calpain-1 and calpain-2 play opposite roles in high IOP-induced ischemic injury and that a selective calpain-2 inhibitor could prevent acute glaucoma-induced RGC death and blindness.
authors.affiliation: Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA, United States.
authors.forename: Yubin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA, United States.
authors.forename: Dulce
authors.initials: D
authors.lastname: Lopez
authors.affiliation: College of Optometry, Western University of Health Sciences, Pomona, CA, United States.
authors.forename: Pinakin Gunvant
authors.initials: PG
authors.lastname: Davey
authors.affiliation: College of Optometry, Western University of Health Sciences, Pomona, CA, United States.
authors.forename: D Joshua
authors.initials: DJ
authors.lastname: Cameron
authors.affiliation: Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA, United States.
authors.forename: Katherine
authors.initials: K
authors.lastname: Nguyen
authors.affiliation: Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Tran
authors.affiliation: Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA, United States.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Marquez
authors.affiliation: Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, United States.
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Bi
authors.affiliation: Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA, United States. Electronic address: mbaudry@westernu.edu.
authors.forename: Michel
authors.initials: M
authors.lastname: Baudry
mesh_terms: D000818:Animals; D002154:Calpain / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D004195:Disease Models, Animal; D005901:Glaucoma / Q000378:metabolism; D007429:Intraocular Pressure / Q000502:physiology; D008810:Mice, Inbred C57BL; D015427:Reperfusion Injury / Q000378:metabolism; D012160:Retina / Q000378:metabolism*; D012165:Retinal Ganglion Cells / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D002154:Calpain; C112682:Capn1 protein, mouse; C570925:Capn2 protein, mouse
keywords: Blindness; Calpain; Glaucoma; Neuroprotection; Retinal ganglion cell