title: ADAMTS-4 promotes neurodegeneration in a mouse model of amyotrophic lateral sclerosis.
abstract: BACKGROUND
  A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) proteoglycanases are specialized in the degradation of chondroitin sulfate proteoglycans and participate in mechanisms mediating neuroplasticity. Despite the beneficial effect of ADAMTS-4 on neurorepair after spinal cord injury, the functions of ADAMTS proteoglycanases in other CNS disease states have not been studied. Therefore, we investigated the expression, effects and associated mechanisms of ADAMTS-4 during amyotrophic lateral sclerosis (ALS) in the SOD1(G93A) mouse model.
  
  
  RESULTS
  ADAMTS-4 expression and activity were reduced in the spinal cord of SOD1(G93A) mice at disease end-stage when compared to WT littermates. To counteract the loss of ADAMTS-4, SOD1(G93A) and WT mice were treated with saline or a recombinant ADAMTS-4 before symptom onset. Administration of ADAMTS-4 worsened the prognosis of SOD1(G93A) mice by accelerating clinical signs of neuromuscular dysfunctions. The worsened prognosis of ADAMTS-4-treated SOD1(G93A) mice was accompanied by increased degradation of perineuronal nets enwrapping motoneurons and increased motoneuron degeneration in the lumbar spinal cord. Motoneurons of ADAMTS-4-treated SOD1(G93A) mice were more vulnerable to degeneration most likely due to the loss of their extracellular matrix envelopes. The decrease of neurotrophic factor production induced by ADAMTS-4 in vitro and in vivo may also contribute to a hostile environment for motoneuron especially when devoid of a net.
  
  
  CONCLUSIONS
  This study suggests that the reduction of ADAMTS-4 activity during the progression of ALS pathology may be an adaptive change to mitigate its neurodegenerative impact in CNS tissues. Therapies compensating the compromized ADAMTS-4 activity are likely not promising approaches for treating ALS.
authors.affiliation: Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland. sighild.lemarchant@uef.fi.
authors.forename: Sighild
authors.initials: S
authors.lastname: Lemarchant
authors.affiliation: Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland. yuriy.pomeshchik@uef.fi.
authors.forename: Yuriy
authors.initials: Y
authors.lastname: Pomeshchik
authors.affiliation: Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland. iurii.kidin@gmail.com.
authors.forename: Iurii
authors.initials: I
authors.lastname: Kidin
authors.affiliation: Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland. virve.karkkainen@kuh.fi.
authors.forename: Virve
authors.initials: V
authors.lastname: Kärkkäinen
authors.affiliation: Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland. piia.valonen@finvector.com.
authors.forename: Piia
authors.initials: P
authors.lastname: Valonen
authors.affiliation: Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland. sarka.lehtonen@uef.fi.
authors.forename: Sarka
authors.initials: S
authors.lastname: Lehtonen
authors.affiliation: Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland. gundars.goldsteins@uef.fi.
authors.forename: Gundars
authors.initials: G
authors.lastname: Goldsteins
authors.affiliation: Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland. tarja.malm@uef.fi.
authors.forename: Tarja
authors.initials: T
authors.lastname: Malm
authors.affiliation: Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland. katja.kanninen@uef.fi.
authors.forename: Katja
authors.initials: K
authors.lastname: Kanninen
authors.affiliation: Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland. jari.koistinaho@uef.fi.
authors.forename: Jari
authors.initials: J
authors.lastname: Koistinaho
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000071121:ADAMTS4 Protein; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D008297:Male; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology*; D011348:Procollagen N-Endopeptidase / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D013482:Superoxide Dismutase; D051722:ADAM Proteins; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein
references.citation: Brain Res. 1993 Sep 3;621(1):111-5
references.pmid: 8221061
references.citation: J Neuroinflammation. 2012;9:53
references.pmid: 22420304
references.citation: Neuroscience. 2010 Sep 1;169(3):1347-63
references.pmid: 20497908
references.citation: J Neurochem. 2004 Apr;89(2):464-73
references.pmid: 15056289
references.citation: CNS Neurol Disord Drug Targets. 2008 Feb;7(1):46-62
references.pmid: 18289031
references.citation: Stem Cells. 2015 May;33(5):1618-29
references.pmid: 25639236
references.citation: Neurobiol Dis. 2014 Apr;64:16-29
references.pmid: 24345324
references.citation: J Neurosci. 2011 Jun 22;31(25):9332-44
references.pmid: 21697383
references.citation: J Neuroinflammation. 2011;8:74
references.pmid: 21711557
references.citation: J Neurochem. 2005 Jun;93(6):1533-41
references.pmid: 15935069
references.citation: Genome Biol. 2011;12(11):233
references.pmid: 22078297
references.citation: J Neurosci. 2012 May 2;32(18):6391-410
references.pmid: 22553043
references.citation: J Biol Chem. 2013 Mar 22;288(12):8299-312
references.pmid: 23404502
references.citation: Front Cell Neurosci. 2014 Feb 28;8:61
references.pmid: 24616665
references.citation: Nature. 2005 Mar 31;434(7033):648-52
references.pmid: 15800625
references.citation: J Neuroinflammation. 2015;12:7
references.pmid: 25592770
references.citation: Mult Scler. 2006 Aug;12(4):386-96
references.pmid: 16900752
references.citation: Exp Neurol. 2008 Apr;210(2):428-40
references.pmid: 18178186
references.citation: Nature. 1993 Mar 4;362(6415):59-62
references.pmid: 8446170
references.citation: Brain Res. 1998 Aug 24;803(1-2):95-104
references.pmid: 9729303
references.citation: J Comp Neurol. 2015 Mar 1;523(4):629-48
references.pmid: 25349050
references.citation: J Neuroinflammation. 2013;10:133
references.pmid: 24176075
references.citation: Arch Ital Biol. 2011 Mar;149(1):65-82
references.pmid: 21412717
references.citation: PLoS One. 2012;7(10):e47793
references.pmid: 23082219
references.citation: Curr Med Chem. 2007;14(22):2318-29
references.pmid: 17896980
references.citation: J Neurochem. 2003 Nov;87(3):752-63
references.pmid: 14535957
references.citation: Hum Mol Genet. 2015 Mar 15;24(6):1655-69
references.pmid: 25410660
references.citation: Neuroreport. 1998 May 11;9(7):1661-5
references.pmid: 9631483
references.citation: Brain Res. 2006 May 9;1088(1):19-30
references.pmid: 16630594
references.citation: J Mol Neurosci. 2015 Apr;55(4):821-9
references.pmid: 25316150
references.citation: PLoS One. 2012;7(10):e47226
references.pmid: 23071766
references.citation: Am J Neurodegener Dis. 2012;1(2):122-9
references.pmid: 23383386
references.citation: Trends Neurosci. 2014 Aug;37(8):433-42
references.pmid: 24927875
references.citation: Neurochem Res. 2001 Dec;26(12):1293-9
references.pmid: 11885780
references.citation: Stem Cells. 2014 Dec;32(12):3163-72
references.pmid: 25113670
references.citation: Glia. 2011 Nov;59(11):1643-57
references.pmid: 21826742
references.citation: Neurosci Lett. 2013 Jun 7;544:25-30
references.pmid: 23562508
references.citation: Exp Neurol. 2004 Aug;188(2):309-15
references.pmid: 15246831
references.citation: Neurosci Lett. 2009 Mar 20;452(3):252-7
references.pmid: 19348733
references.citation: Cochrane Database Syst Rev. 2012;3:CD001447
references.pmid: 22419278
references.citation: Glia. 2009 Oct;57(13):1386-92
references.pmid: 19229990
references.citation: Nature. 2005 Mar 31;434(7033):644-8
references.pmid: 15800624
references.citation: Biochim Biophys Acta. 2015 Apr;1852(4):679-84
references.pmid: 25193032
references.citation: Neurobiol Dis. 2014 Jun;66:28-42
references.pmid: 24576594
references.citation: Acta Pharmacol Sin. 2015 Feb;36(2):149-57
references.pmid: 25544363
references.citation: Matrix Biol. 2015 May-Jul;44-46:70-6
references.pmid: 25622912
references.citation: J Mol Med (Berl). 2010 Dec;88(12):1203-11
references.pmid: 20652528
references.citation: J Neurosci Res. 2008 Aug 15;86(11):2512-23
references.pmid: 18438943
references.citation: J Autoimmun. 2006 Feb;26(1):16-23
references.pmid: 16303287
references.citation: J Neurosci. 2015 May 13;35(19):7538-51
references.pmid: 25972179
references.citation: J Biol Chem. 2006 Jun 30;281(26):17789-800
references.pmid: 16644727
references.citation: Neuropathol Appl Neurobiol. 2014 Feb;40(1):26-59
references.pmid: 24438519