title: Rescue of Glaucomatous Neurodegeneration by Differentially Modulating Neuronal Endoplasmic Reticulum Stress Molecules.
abstract: Axon injury is an early event in neurodegenerative diseases that often leads to retrograde neuronal cell death and progressive permanent loss of vital neuronal functions. The connection of these two obviously sequential degenerative events, however, is elusive. Deciphering the upstream signals that trigger the neurodegeneration cascades in both neuronal soma and axon would be a key step toward developing the effective neuroprotectants that are greatly needed in the clinic. We showed previously that optic nerve injury-induced neuronal endoplasmic reticulum (ER) stress plays an important role in retinal ganglion cell (RGC) death. Using two in vivo mouse models of optic neuropathies (traumatic optic nerve injury and glaucoma) and adeno-associated virus-mediated RGC-specific gene targeting, we now show that differential manipulation of unfolded protein response pathways in opposite directions-inhibition of eukaryotic translation initiation factor 2α-C/EBP homologous protein and activation of X-box binding protein 1-promotes both RGC axons and somata survival and preserves visual function. Our results indicate that axon injury-induced neuronal ER stress plays an important role in both axon degeneration and neuron soma death. Neuronal ER stress is therefore a promising therapeutic target for glaucoma and potentially other types of neurodegeneration.
  
  
  
  Neuron soma and axon degeneration have distinct molecular mechanisms although they are clearly connected after axon injury. We previously demonstrated that axon injury induces neuronal endoplasmic reticulum (ER) stress and that manipulation of ER stress molecules synergistically promotes neuron cell body survival. Here we investigated the possibility that ER stress also plays a role in axon degeneration and whether ER stress modulation preserves neuronal function in neurodegenerative diseases. Our results suggest that neuronal ER stress is a general mechanism of degeneration for both neuronal cell body and axon, and that therapeutic targeting of ER stress produces significant functional recovery.
authors.affiliation: Center for Neural Repair and Rehabilitation, Shriners Hospitals Pediatric Research Center.
authors.forename: Liu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Center for Neural Repair and Rehabilitation, Shriners Hospitals Pediatric Research Center, Department of Ophthalmology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: Shaohua
authors.identifier: 0000-0002-6267-3054
authors.initials: S
authors.lastname: Li
authors.affiliation: Center for Neural Repair and Rehabilitation, Shriners Hospitals Pediatric Research Center.
authors.forename: Linqing
authors.identifier: 0000-0002-1489-0548
authors.initials: L
authors.lastname: Miao
authors.affiliation: Center for Neural Repair and Rehabilitation, Shriners Hospitals Pediatric Research Center.
authors.forename: Haoliang
authors.initials: H
authors.lastname: Huang
authors.affiliation: Center for Neural Repair and Rehabilitation, Shriners Hospitals Pediatric Research Center.
authors.forename: Feisi
authors.initials: F
authors.lastname: Liang
authors.affiliation: Center for Neural Repair and Rehabilitation, Shriners Hospitals Pediatric Research Center.
authors.forename: Xiuyin
authors.initials: X
authors.lastname: Teng
authors.affiliation: Center for Neural Repair and Rehabilitation, Shriners Hospitals Pediatric Research Center, Department of Neurology, Affiliated Hospital of Qingdao University, Qingdao 266000, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
authors.affiliation: Sol Sherry Thrombosis Research Center, and.
authors.forename: Qizhao
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Sol Sherry Thrombosis Research Center, and.
authors.forename: Weidong
authors.identifier: 0000-0003-4295-1536
authors.initials: W
authors.lastname: Xiao
authors.affiliation: Southern California College of Optometry, Marshall B. Ketchum University, Fullerton, California 92831.
authors.forename: William H
authors.initials: WH
authors.lastname: Ridder
authors.affiliation: Amyotrophic Lateral Sclerosis Innovation Hub, Development Sciences, Biogen Idec, Cambridge, Massachusetts 02142.
authors.forename: Toby A
authors.initials: TA
authors.lastname: Ferguson
authors.affiliation: Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts 02114, and.
authors.forename: Dong Feng
authors.initials: DF
authors.lastname: Chen
authors.affiliation: Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037.
authors.forename: Randal J
authors.initials: RJ
authors.lastname: Kaufman
authors.affiliation: Center for Neural Repair and Rehabilitation, Shriners Hospitals Pediatric Research Center, Department of Anatomy and Cell Biology, School of Medicine, Temple University, Philadelphia, Pennsylvania 19140, yanghu@temple.edu.
authors.forename: Yang
authors.identifier: 0000-0002-7980-1649
authors.initials: Y
authors.lastname: Hu
mesh_terms: D000818:Animals; D059865:Endoplasmic Reticulum Stress; D005260:Female; D005901:Glaucoma / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D012162:Retinal Degeneration / Q000378:metabolism*; D012165:Retinal Ganglion Cells / Q000378:metabolism; D056811:Unfolded Protein Response
chemical_list: D009419:Nerve Tissue Proteins
keywords: ER stress; axon degeneration; glaucoma; neuroprotection; optic nerve; retinal ganglion cell