title: GDE2 is essential for neuronal survival in the postnatal mammalian spinal cord.
abstract: Glycerophosphodiester phosphodiesterase 2 (GDE2) is a six-transmembrane protein that cleaves glycosylphosphatidylinositol (GPI) anchors to regulate GPI-anchored protein activity at the cell surface. In the developing spinal cord, GDE2 utilizes its enzymatic function to regulate the production of specific classes of motor neurons and interneurons; however, GDE2's roles beyond embryonic neurogenesis have yet to be defined.
  
  
  
  Using a panel of histological, immunohistochemical, electrophysiological, behavioral, and biochemistry techniques, we characterized the postnatal Gde2-/-mouse for evidence of degenerative neuropathology. A conditional deletion of Gde2 was used to study the temporal requirements for GDE2 in neuronal survival. Biochemical approaches identified deficits in the processing of GPI-anchored GDE2 substrates in the SOD1G93Amouse model of familial Amyotrophic Lateral Sclerosis that shows robust motor neuron degeneration.
  
  
  
  Here we show that GDE2 expression continues postnatally, and adult mice lacking GDE2 exhibit a slow, progressive neuronal degeneration with pathologies similar to human neurodegenerative disease. Early phenotypes include vacuolization, microgliosis, cytoskeletal accumulation, and lipofuscin deposition followed by astrogliosis and cell death. Remaining motor neurons exhibit peripheral motor unit restructuring causing behavioral motor deficits. Genetic ablation of GDE2 after embryonic neurogenesis is complete still elicits degenerative pathology, signifying that GDE2's requirement for neuronal survival is distinct from its involvement in neuronal differentiation. Unbiased screens identify impaired processing of Glypican 4 and 6 in Gde2 null animals, and Glypican release is markedly reduced in SOD1G93Amice.
  
  
  
  This study identifies a novel function for GDE2 in neuronal survival and implicates deregulated GPI-anchored protein activity in pathways mediating neurodegeneration. These findings provide new molecular insight for neuropathologies found in multiple disease settings, and raise the possibility of GDE2 hypofunctionality as a component of neurodegenerative disease.
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, 725 N Wolfe Street, PCTB 1004, Baltimore, MD, 21205, USA.
authors.forename: Clinton
authors.initials: C
authors.lastname: Cave
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, 725 N Wolfe Street, PCTB 1004, Baltimore, MD, 21205, USA.|University of Utah, BPRB 390D South 2030 East, Salt Lake City, UT, 84112, USA.
authors.forename: Sungjin
authors.initials: S
authors.lastname: Park
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, 725 N Wolfe Street, PCTB 1004, Baltimore, MD, 21205, USA.|Bascom Palmer Eye Institute, 900 NW 17th St, Miami, FL, 33136, USA.
authors.forename: Marianeli
authors.initials: M
authors.lastname: Rodriguez
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, 725 N Wolfe Street, PCTB 1004, Baltimore, MD, 21205, USA.
authors.forename: Mai
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, USA.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Hoke
authors.affiliation: Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, USA.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Pletnikov
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, 725 N Wolfe Street, PCTB 1004, Baltimore, MD, 21205, USA. ssockan1@jhmi.edu.
authors.forename: Shanthini
authors.initials: S
authors.lastname: Sockanathan
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016923:Cell Death / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics; D002470:Cell Survival; D004195:Disease Models, Animal; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism*; D055495:Neurogenesis / Q000502:physiology; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism*
chemical_list: D010727:Phosphoric Diester Hydrolases; C038133:glycerophosphodiester phosphodiesterase
keywords: GDE2; GPI-Anchor; Motor neuron; Neurodegeneration