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Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2017

Open Access 01-12-2017 | Research article

GDE2 is essential for neuronal survival in the postnatal mammalian spinal cord

Authors: Clinton Cave, Sungjin Park, Marianeli Rodriguez, Mai Nakamura, Ahmet Hoke, Mikhail Pletnikov, Shanthini Sockanathan

Published in: Molecular Neurodegeneration | Issue 1/2017

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Abstract

Background

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.

Method

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 SOD1 G93A mouse model of familial Amyotrophic Lateral Sclerosis that shows robust motor neuron degeneration.

Results

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 SOD1 G93A mice.

Conclusions

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.
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Literature
1.
2.
3.
Corda D, Mosca MG, Ohshima N, Grauso L, Yanaka N, Mariggiò S. The emerging physiological roles of the glycerophosphodiesterase family. FEBS J. 2014;281:998–1016.CrossRefPubMed
4.
Yanaka N. Mammalian glycerophosphodiester phosphodiesterases. Biosci Biotechnol Biochem. 2007;71:1811–8.CrossRefPubMed
5.
Corda D, Kudo T, Zizza P, Iurisci C, Kawai E, Kato N, Yanaka N, Mariggiò S. The developmentally regulated osteoblast phosphodiesterase GDE3 is glycerophosphoinositol-specific and modulates cell growth. J Biol Chem. 2009;284:24848–56.CrossRefPubMedPubMedCentral
6.
Rao M, Sockanathan S. Transmembrane protein GDE2 induces motor neuron differentiation in vivo. Science. 2005;309:2212–5.CrossRefPubMed
7.
Yan Y, Sabharwal P, Rao M, Sockanathan S. The antioxidant enzyme Prdx1 controls neuronal differentiation by thiol-redox-dependent activation of GDE2. Cell. 2009;138:1209–21.CrossRefPubMedPubMedCentral
8.
Sabharwal P, Lee C, Park S, Rao M, Sockanathan S. GDE2 regulates subtype-specific motor neuron generation through inhibition of Notch signaling. Neuron. 2011;71:1058–70.CrossRefPubMedPubMedCentral
9.
Park S, Lee C, Sabharwal P, Zhang M, Meyers CLF, Sockanathan S. GDE2 Promotes Neurogenesis by Glycosylphosphatidylinositol-Anchor Cleavage of RECK. Science. 2013;339:324–8.CrossRefPubMedPubMedCentral
10.
Rodriguez M, Choi J, Park S, Sockanathan S. Gde2 regulates cortical neuronal identity by controlling the timing of cortical progenitor differentiation. Development. 2012;139:3870–9.CrossRefPubMed
11.
12.
13.
Matas-Rico E, van Veen M, Leyton-Puig D, van den Berg J, Koster J, Kedziora KM, Molenaar B, Weerts MJA, de Rink I, Medema RH, Giepmans BNG, Perrakis A, Jalink K, Versteeg R, Moolenaar WH. Glycerophosphodiesterase GDE2 promotes neuroblastoma differentiation through glypican release and is a marker of clinical outcome. Cancer Cell. 2016;30:548–62.CrossRefPubMed
14.
Radford HE, Mallucci GR. The role of GPI-anchored PrP C in mediating the neurotoxic effect of scrapie prions in neurons. Curr Issues Mol Biol. 2010;12:119–27.PubMed
15.
Yang LB, Li R, Meri S, Rogers J, Shen Y. Deficiency of complement defense protein CD59 may contribute to neurodegeneration in Alzheimer’s disease. J Neurosci. 2000;20:7505–9.PubMed
16.
Watanabe N. Glypican-1 as an A binding HSPG in the human brain: Its localization in DIG domains and possible roles in the pathogenesis of Alzheimer’s disease. FASEB J. 2004;18(9):1013–5.PubMed
17.
Mani K, Cheng F, Fransson L-A. Defective nitric oxide-dependent, deaminative cleavage of glypican-1 heparan sulfate in Niemann-Pick C1 fibroblasts. Glycobiology. 2006;16:711–8.CrossRefPubMed
18.
Glas M, Popp B, Angele B, Koedel U, Chahli C, Schmalix WA, Anneser JM, Pfister HW, Lorenzl S. A role for the urokinase-type plasminogen activator system in amyotrophic lateral sclerosis. Exp Neurol. 2007;207:350–6.CrossRefPubMed
19.
Lagier-Tourenne C, Polymenidou M, Hutt KR, Vu AQ, Baughn M, Huelga SC, Clutario KM, Ling S-C, Liang TY, Mazur C, Wancewicz E, Kim AS, Watt A, Freier S, Hicks GG, Donohue JP, Shiue L, Bennett CF, Ravits J, Cleveland DW, Yeo GW. Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs. Nat Neurosci. 2012;15:1488–97.CrossRefPubMedPubMedCentral
20.
Wong PC, Cai H, Borchelt DR, Price DL. Genetically engineered mouse models of neurodegenerative diseases. Nat Neurosci. 2002;5:633–9.CrossRefPubMed
21.
Rothstein JD. Current hypotheses for the underlying biology of amyotrophic lateral sclerosis. Ann Neurol. 2009;65 Suppl 1:S3–9.CrossRefPubMed
22.
Schaeren-Wiemers N, Gerfin-Moser A. A single protocol to detect transcripts of various types and expression levels in neural tissue and cultured cells: in situ hybridization using digoxigenin-labelled cRNA probes. Histochemistry. 1993;100:431–40.CrossRefPubMed
23.
Zhao P, Nairn AV, Hester S, Moremen KW, O’Regan RM, Oprea G, Wells L, Pierce M, Abbott KL. Proteomic identification of glycosylphosphatidylinositol anchor-dependent membrane proteins elevated in breast carcinoma. J Biol Chem. 2012;287:25230–40.CrossRefPubMedPubMedCentral
24.
Shevchenko A, Wilm M, Vorm O, Mann M. Mass spectrometric sequencing of proteins silver-stained polyacrylamide gels. Anal Chem. 1996;68:850–8.CrossRefPubMed
25.
26.
Eng JK, McCormack AL, Yates JR. An approach to correlate tandem mass spectral data of peptides with amino acid sequences in a protein database. J Am Soc Mass Spectrom. 1994;5:976–89.CrossRefPubMed
27.
Cahoy JD, Emery B, Kaushal A, Foo LC, Zamanian JL, Christopherson KS, Xing Y, Lubischer JL, Krieg PA, Krupenko SA, Thompson WJ, Barres BA. A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J Neurosci. 2008;28:264–78.CrossRefPubMed
28.
Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O’Keeffe S, Phatnani HP, Guarnieri P, Caneda C, Ruderisch N, Deng S, Liddelow SA, Zhang C, Daneman R, Maniatis T, Barres BA, Wu JQ. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci. 2014;34:11929–47.CrossRefPubMedPubMedCentral
29.
30.
Kreutzberg GW. Microglia: a sensor for pathological events in the CNS. Trends Neurosci. 1996;19:312–8.CrossRefPubMed
31.
Barres BA. The mystery and magic of glia: a perspective on their roles in health and disease. Neuron. 2008;60:430–40.CrossRefPubMed
32.
Xiao S, McLean J, Robertson J. Neuronal intermediate filaments and ALS: a new look at an old question. Biochim Biophys Acta. 2006;1762:1001–12.CrossRefPubMed
33.
Gray E, Rice C, Nightingale H, Ginty M, Hares K, Kemp K, Cohen N, Love S, Scolding N, Wilkins A. Accumulation of cortical hyperphosphorylated neurofilaments as a marker of neurodegeneration in multiple sclerosis. Mult Scler. 2013;19:153–61.CrossRefPubMed
34.
Lalonde R, Strazielle C. Neurobehavioral characteristics of mice with modified intermediate filament genes. Rev Neurosci. 2003;14:369–85.CrossRefPubMed
35.
Bruijn LI, Miller TM, Cleveland DW. Unraveling the mechanisms involved in motor neuron degeneration in ALS. Annu Rev Neurosci. 2004;27:723–49.CrossRefPubMed
36.
Schnell SA, Staines WA, Wessendorf MW. Reduction of lipofuscin-like autofluorescence in fluorescently labeled tissue. J Histochem Cytochem. 1999;47:719–30.CrossRefPubMed
37.
Frank A, Christensen A. Localization of acid phosphatase in lipofuscin granules and possible autophagic vacuoles in interstitial cells of the guinea pig testis. J Cell Biol. 1968;36:1–13.CrossRefPubMedCentral
38.
39.
Mink JW, Augustine EF, Adams HR, Marshall FJ, Kwon JM. Classification and natural history of the neuronal ceroid lipofuscinoses. J Child Neurol. 2013;28:1101–5.CrossRefPubMedPubMedCentral
40.
Kanning KC, Kaplan A, Henderson CE. Motor neuron diversity in development and disease. Annu Rev Neurosci. 2010;33:409–40.CrossRefPubMed
41.
Friese A, Kaltschmidt JA, Ladle DR, Sigrist M, Jessell TM, Arber S. Gamma and alpha motor neurons distinguished by expression of transcription factor Err3. Proc Natl Acad Sci. 2009;106:13588–93.CrossRefPubMedPubMedCentral
42.
Keswani SC, Jack C, Zhou C, Höke A. Establishment of a rodent model of HIV-associated sensory neuropathy. J Neurosci. 2006;26:10299–304.CrossRefPubMed
43.
Shefner JM, Cudkowicz M, Brown RH. Motor unit number estimation predicts disease onset and survival in a transgenic mouse model of amyotrophic lateral sclerosis. Muscle Nerve. 2006;34:603–7.CrossRefPubMed
44.
Shefner JM. Recent MUNE studies in animal models of motor neuron disease. Suppl Clin Neurophysiol. 2009;60:203–8.CrossRefPubMed
45.
46.
Filali M, Lalonde R, Rivest S. Sensorimotor and cognitive functions in a SOD1(G37R) transgenic mouse model of amyotrophic lateral sclerosis. Behav Brain Res. 2011;225:215–21.CrossRefPubMed
47.
Brooks SP, Dunnett SB. Tests to assess motor phenotype in mice: a user’s guide. Nat Rev Neurosci. 2009;10:519–29.CrossRefPubMed
48.
Le Bars D, Gozariu M, Cadden SW. Animal models of nociception. Pharmacol Rev. 2001;53:597–652.PubMed
49.
Badea TC, Wang Y, Nathans J. A noninvasive genetic/pharmacologic strategy for visualizing cell morphology and clonal relationships in the mouse. J Neurosci. 2003;23:2314–22.PubMed
50.
Kim K, Jarry H, Knoke I, Seong JY, Leonhardt S, Wuttke W. Competitive PCR for quantitation of gonadotropin-releasing hormone mRNA level in a single micropunch of the rat preoptic area. Mol Cell Endocrinol. 1993;97:153–8.CrossRefPubMed
51.
Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD, Caliendo J, Hentati A, Kwon YW, Deng HX. Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation. Science. 1994;264:1772–5.CrossRefPubMed
52.
Vinsant S, Mansfield C, Jimenez-Moreno R, Moore VDG, Yoshikawa M, Hampton TG, Prevette D, Caress J, Oppenheim RW, Milligan C. Characterization of early pathogenesis in the SOD1G93A mouse model of ALS: Part II, results and discussion. Brain Behav. 2013;3:431–57.CrossRefPubMedPubMedCentral
53.
Vinsant S, Mansfield C, Jimenez-Moreno R, Del Gaizo Moore V, Yoshikawa M, Hampton TG, Prevette D, Caress J, Oppenheim RW, Milligan C. Characterization of early pathogenesis in the SOD1(G93A) mouse model of ALS: part I, background and methods. Brain Behav. 2013;3:335–50.CrossRefPubMedPubMedCentral
54.
Hooper NM, Turner AJ. Ectoenzymes of the kidney microvillar membrane. Differential solubilization by detergents can predict a glycosyl-phosphatidylinositol membrane anchor. Biochem J. 1988;250:865–9.CrossRefPubMedPubMedCentral
55.
Yamanaka K, Chun SJ, Boillee S, Fujimori-Tonou N, Yamashita H, Gutmann DH, Takahashi R, Misawa H, Cleveland DW. Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nat Neurosci. 2008;11:251–3.CrossRefPubMedPubMedCentral
56.
Lee Y, Morrison BM, Li Y, Lengacher S, Farah MH, Hoffman PN, Liu Y, Tsingalia A, Jin L, Zhang P-W, Pellerin L, Magistretti PJ, Rothstein JD. Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature. 2012;487:443–8.CrossRefPubMedPubMedCentral
57.
Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, Merry KM, Shi Q, Rosenthal A, Barres BA, Lemere CA, Selkoe DJ, Stevens B. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 2016;352:712–6.CrossRefPubMedPubMedCentral
58.
Chaudhry V, Glass JD, Griffin JW. Wallerian degeneration in peripheral nerve disease. Neurol Clin. 1992;10:613–27.PubMed
59.
Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, Sivertsson Å, Kampf C, Sjöstedt E, Asplund A, Olsson I, Edlund K, Lundberg E, Navani S, Szigyarto CA-K, Odeberg J, Djureinovic D, Takanen JO, Hober S, Alm T, Edqvist P-H, Berling H, Tegel H, Mulder J, Rockberg J, Nilsson P, Schwenk JM, Hamsten M, von Feilitzen K, Forsberg M, et al. Proteomics. Tissue-based map of the human proteome. Science. 2015. doi:10.​1126/​science.​1260419.PubMed
60.
Yan Y, Wladyka C, Fujii J, Sockanathan S. Prdx4 is a compartment-specific H2O2 sensor that regulates neurogenesis by controlling surface expression of GDE2. Nat Commun. 2015;6:7006.CrossRefPubMedPubMedCentral
61.
62.
Simpson EP, Henry YK, Henkel JS, Smith RG, Appel SH. Increased lipid peroxidation in sera of ALS patients: a potential biomarker of disease burden. Neurology. 2004;62:1758–65.CrossRefPubMed
63.
Markesbery WR, Lovell MA. Four-hydroxynonenal, a product of lipid peroxidation, is increased in the brain in Alzheimer’s disease. Neurobiol Aging. 1998;19:33–6.CrossRefPubMed
64.
Alam ZI, Daniel SE, Lees AJ, Marsden DC, Jenner P, Halliwell B. A generalised increase in protein carbonyls in the brain in Parkinson’s but not incidental Lewy body disease. J Neurochem. 1997;69:1326–9.CrossRefPubMed
65.
Novarino G, Fenstermaker AG, Zaki MS, Hofree M, Silhavy JL, Heiberg AD, Abdellateef M, Rosti B, Scott E, Mansour L, Masri A, Kayserili H, Al-Aama JY, Abdel-Salam GM, Karminejad A, Kara M, Kara B, Bozorgmehri B, Ben-Omran T, Mojahedi F, Mahmoud IG, Bouslam N, Bouhouche A, Benomar A, Hanein S, Raymond L, Forlani S, Mascaro M, Selim L, Shehata N, et al. Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science. 2014;343:506–11.CrossRefPubMedPubMedCentral
66.
Zanoteli E, Maximino JR, Conti Reed U, Chadi G. Spinal muscular atrophy: from animal model to clinical trial. Funct Neurol. 2010;25:73–9.PubMed
67.
Fink JK. Hereditary spastic paraplegia: clinical principles and genetic advances. Semin Neurol. 2014;34:293–305.CrossRefPubMed
68.
Rabin SJ, Kim JMH, Baughn M, Libby RT, Kim YJ, Fan Y, Libby RT, La Spada A, Stone B, Ravits J. Sporadic ALS has compartment-specific aberrant exon splicing and altered cell-matrix adhesion biology. Hum Mol Genet. 2010;19:313–28.CrossRefPubMed
Metadata
Title
GDE2 is essential for neuronal survival in the postnatal mammalian spinal cord
Authors
Clinton Cave
Sungjin Park
Marianeli Rodriguez
Mai Nakamura
Ahmet Hoke
Mikhail Pletnikov
Shanthini Sockanathan
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2017
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/s13024-017-0148-1

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