Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2016

Open Access 01-12-2016 | Research article

ADAMTS-4 promotes neurodegeneration in a mouse model of amyotrophic lateral sclerosis

Authors: Sighild Lemarchant, Yuriy Pomeshchik, Iurii Kidin, Virve Kärkkäinen, Piia Valonen, Sarka Lehtonen, Gundars Goldsteins, Tarja Malm, Katja Kanninen, Jari Koistinaho

Published in: Molecular Neurodegeneration | Issue 1/2016

Login to get access

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 SOD1G93A mouse model.

Results

ADAMTS-4 expression and activity were reduced in the spinal cord of SOD1G93A mice at disease end-stage when compared to WT littermates. To counteract the loss of ADAMTS-4, SOD1G93A and WT mice were treated with saline or a recombinant ADAMTS-4 before symptom onset. Administration of ADAMTS-4 worsened the prognosis of SOD1G93A mice by accelerating clinical signs of neuromuscular dysfunctions. The worsened prognosis of ADAMTS-4-treated SOD1G93A 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 SOD1G93A 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.
Literature
1.
Lemarchant S, Pruvost M, Montaner J, Emery E, Vivien D, Kanninen K, et al. ADAMTS proteoglycanases in the physiological and pathological central nervous system. J Neuroinflammation. 2013;10:133.PubMedCentralCrossRefPubMed
2.
Hamel MG, Mayer J, Gottschall PE. Altered production and proteolytic processing of brevican by transforming growth factor beta in cultured astrocytes. J Neurochem. 2005;93:1533–41.CrossRefPubMed
3.
Howell MD, Torres-Collado AX, Iruela-Arispe ML, Gottschall PE. Selective decline of synaptic protein levels in the frontal cortex of female mice deficient in the extracellular metalloproteinase ADAMTS1. PLoS One. 2012;7:e47226.PubMedCentralCrossRefPubMed
4.
Krstic D, Rodriguez M, Knuesel I. Regulated proteolytic processing of Reelin through interplay of tissue plasminogen activator (tPA), ADAMTS-4, ADAMTS-5, and their modulators. PLoS One. 2012;7:e47793.PubMedCentralCrossRefPubMed
5.
Lemarchant S, Pruvost M, Hébert M, Gauberti M, Hommet Y, Briens A, et al. tPA promotes ADAMTS-4-induced CSPG degradation, thereby enhancing neuroplasticity following spinal cord injury. Neurobiol Dis. 2014;66:28–42.CrossRefPubMed
6.
Tauchi R, Imagama S, Natori T, Ohgomori T, Muramoto A, Shinjo R, et al. The endogenous proteoglycan-degrading enzyme ADAMTS-4 promotes functional recovery after spinal cord injury. J Neuroinflammation. 2012;9:53.PubMedCentralCrossRefPubMed
7.
8.
Reid MJ, Cross AK, Haddock G, Allan SM, Stock CJ, Woodroofe MN, et al. ADAMTS-9 expression is up-regulated following transient middle cerebral artery occlusion (tMCAo) in the rat. Neurosci Lett. 2009;452:252–7.CrossRefPubMed
9.
Cross AK, Haddock G, Surr J, Plumb J, Bunning RA, Buttle DJ, et al. Differential expression of ADAMTS-1, −4, −5 and TIMP-3 in rat spinal cord at different stages of acute experimental autoimmune encephalomyelitis. J Autoimmun. 2006;26:16–23.CrossRefPubMed
10.
Demircan K, Yonezawa T, Takigawa T, Topcu V, Erdogan S, Ucar F, et al. ADAMTS1, ADAMTS5, ADAMTS9 and aggrecanase-generated proteoglycan fragments are induced following spinal cord injury in mouse. Neurosci Lett. 2013;544:25–30.CrossRefPubMed
11.
Ajroud-Driss S, Siddique T. Sporadic and hereditary amyotrophic lateral sclerosis (ALS). Biochim Biophys Acta. 1852;2015:679–84.
12.
Ticozzi N, Tiloca C, Morelli C, Colombrita C, Poletti B, Doretti A, et al. Genetics of familial Amyotrophic lateral sclerosis. Arch Ital Biol. 2011;149:65–82.PubMed
13.
Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993;362:59–62.CrossRefPubMed
14.
Vucic S, Rothstein JD, Kiernan MC. Advances in treating amyotrophic lateral sclerosis: insights from pathophysiological studies. Trends Neurosci. 2014;37:433–42.CrossRefPubMed
15.
Miller RG, Mitchell JD, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev. 2012;3:CD001447.PubMed
16.
17.
Salter RC, Ashlin TG, Kwan AP, Ramji DP. ADAMTS proteases: key roles in atherosclerosis? J Mol Med (Berl). 2010;88:1203–11.CrossRef
18.
Forostyak S, Homola A, Turnovcova K, Svitil P, Jendelova P, Sykova E. Intrathecal delivery of mesenchymal stromal cells protects the structure of altered perineuronal nets in SOD1 rats and amends the course of ALS. Stem Cells. 2014;32:3163–72.PubMedCentralCrossRefPubMed
19.
Wang D, Ichiyama RM, Zhao R, Andrews MR, Fawcett JW. Chondroitinase combined with rehabilitation promotes recovery of forelimb function in rats with chronic spinal cord injury. J Neurosci. 2011;31:9332–44.CrossRefPubMed
20.
Levy C, Brooks JM, Chen J, Su J, Fox MA. Cell-specific and developmental expression of lectican-cleaving proteases in mouse hippocampus and neocortex. J Comp Neurol. 2015;523:629–48.CrossRefPubMed
21.
Cross AK, Haddock G, Stock CJ, Allan S, Surr J, Bunning RA, et al. ADAMTS-1 and −4 are up-regulated following transient middle cerebral artery occlusion in the rat and their expression is modulated by TNF in cultured astrocytes. Brain Res. 2006;1088:19–30.CrossRefPubMed
22.
Haddock G, Cross AK, Plumb J, Surr J, Buttle DJ, Bunning RA, et al. Expression of ADAMTS-1, −4, −5 and TIMP-3 in normal and multiple sclerosis CNS white matter. Mult Scler. 2006;12:386–96.CrossRefPubMed
23.
Hamel MG, Ajmo JM, Leonardo CC, Zuo F, Sandy JD, Gottschall PE. Multimodal signaling by the ADAMTSs (a disintegrin and metalloproteinase with thrombospondin motifs) promotes neurite extension. Exp Neurol. 2008;210:428–40.PubMedCentralCrossRefPubMed
24.
Glasson SS, Askew R, Sheppard B, Carito B, Blanchet T, Ma HL, et al. Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature. 2005;434:644–8.CrossRefPubMed
25.
Stanton H, Rogerson FM, East CJ, Golub SB, Lawlor KE, Meeker CT, et al. ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro. Nature. 2005;434:648–52.CrossRefPubMed
26.
Mizuno H, Warita H, Aoki M, Itoyama Y. Accumulation of chondroitin sulfate proteoglycans in the microenvironment of spinal motor neurons in amyotrophic lateral sclerosis transgenic rats. J Neurosci Res. 2008;86:2512–23.CrossRefPubMed
27.
Gottschall PE, Howell MD. ADAMTS expression and function in central nervous system injury and disorders. Matrix Biol. 2015;44-46:70-6.
28.
Burnside ER, Bradbury EJ. Manipulating the extracellular matrix and its role in brain and spinal cord plasticity and repair. Neuropathol Appl Neurobiol. 2014;40:26–59.CrossRefPubMed
29.
Suttkus A, Rohn S, Jäger C, Arendt T, Morawski M. Neuroprotection against iron-induced cell death by perineuronal nets - an in vivo analysis of oxidative stress. Am J Neurodegener Dis. 2012;1:122–9.PubMedCentralPubMed
30.
Morawski M, Brückner G, Jäger C, Seeger G, Arendt T. Neurons associated with aggrecan-based perineuronal nets are protected against tau pathology in subcortical regions in Alzheimer’s disease. Neuroscience. 2010;169:1347–63.CrossRefPubMed
31.
Morawski M, Brückner MK, Riederer P, Brückner G, Arendt T. Perineuronal nets potentially protect against oxidative stress. Exp Neurol. 2004;188:309–15.CrossRefPubMed
32.
Deepa SS, Carulli D, Galtrey C, Rhodes K, Fukuda J, Mikami T, et al. Composition of perineuronal net extracellular matrix in rat brain: a different disaccharide composition for the net-associated proteoglycans. J Biol Chem. 2006;281:17789–800.CrossRefPubMed
33.
Tovar-Y-Romo LB, Ramírez-Jarquín UN, Lazo-Gómez R, Tapia R. Trophic factors as modulators of motor neuron physiology and survival: implications for ALS therapy. Front Cell Neurosci. 2014;8:61.PubMedCentralCrossRefPubMed
34.
Schulte-Herbrüggen O, Braun A, Rochlitzer S, Jockers-Scherübl MC, Hellweg R. Neurotrophic factors--a tool for therapeutic strategies in neurological, neuropsychiatric and neuroimmunological diseases? Curr Med Chem. 2007;14:2318–29.CrossRefPubMed
35.
Sen A, Nelson TJ, Alkon DL. ApoE4 and Aβ Oligomers Reduce BDNF Expression via HDAC Nuclear Translocation. J Neurosci. 2015;35:7538–51.CrossRefPubMed
36.
Corbett GT, Roy A, Pahan K. Sodium phenylbutyrate enhances astrocytic neurotrophin synthesis via protein kinase C (PKC)-mediated activation of cAMP-response element-binding protein (CREB): implications for Alzheimer disease therapy. J Biol Chem. 2013;288:8299–312.PubMedCentralCrossRefPubMed
37.
Zaheer A, Yorek MA, Lim R. Effects of glia maturation factor overexpression in primary astrocytes on MAP kinase activation, transcription factor activation, and neurotrophin secretion. Neurochem Res. 2001;26:1293–9.CrossRefPubMed
38.
Woodbury D, Schaar DG, Ramakrishnan L, Black IB. Novel structure of the human GDNF gene. Brain Res. 1998;803:95–104.CrossRefPubMed
39.
40.
Gao Y, Su J, Guo W, Polich ED, Magyar DP, Xing Y, et al. Inhibition of miR-15a Promotes BDNF Expression and Rescues Dendritic Maturation Deficits in MeCP2-Deficient Neurons. Stem Cells. 2015;33:1618–29.CrossRefPubMed
41.
Huang W, Liu X, Cao J, Meng F, Li M, Chen B, et al. miR-134 regulates ischemia/reperfusion injury-induced neuronal cell death by regulating CREB signaling. J Mol Neurosci. 2015;55:821–9.CrossRefPubMed
42.
Skaper SD. The biology of neurotrophins, signalling pathways, and functional peptide mimetics of neurotrophins and their receptors. CNS Neurol Disord Drug Targets. 2008;7:46–62.CrossRefPubMed
43.
Nishio T, Sunohara N, Furukawa S. Neutrophin switching in spinal motoneurons of amyotrophic lateral sclerosis. Neuroreport. 1998;9:1661–5.CrossRefPubMed
44.
Seeburger JL, Tarras S, Natter H, Springer JE. Spinal cord motoneurons express p75NGFR and p145trkB mRNA in amyotrophic lateral sclerosis. Brain Res. 1993;621:111–5.CrossRefPubMed
45.
Pehar M, Cassina P, Vargas MR, Castellanos R, Viera L, Beckman JS, et al. Astrocytic production of nerve growth factor in motor neuron apoptosis: implications for amyotrophic lateral sclerosis. J Neurochem. 2004;89:464–73.CrossRefPubMed
46.
Turner BJ, Cheah IK, Macfarlane KJ, Lopes EC, Petratos S, Langford SJ, et al. Antisense peptide nucleic acid-mediated knockdown of the p75 neurotrophin receptor delays motor neuron disease in mutant SOD1 transgenic mice. J Neurochem. 2003;87:752–63.CrossRefPubMed
47.
Cragnolini AB, Huang Y, Gokina P, Friedman WJ. Nerve growth factor attenuates proliferation of astrocytes via the p75 neurotrophin receptor. Glia. 2009;57:1386–92.PubMedCentralCrossRefPubMed
48.
Pollari E, Savchenko E, Jaronen M, Kanninen K, Malm T, Wojciechowski S, et al. Granulocyte colony stimulating factor attenuates inflammation in a mouse model of amyotrophic lateral sclerosis. J Neuroinflammation. 2011;8:74.PubMedCentralCrossRefPubMed
49.
Moujalled D, James JL, Yang S, Zhang K, Duncan C, Moujalled DM, et al. Phosphorylation of hnRNP K by cyclin-dependent kinase 2 controls cytosolic accumulation of TDP-43. Hum Mol Genet. 2015;24:1655–69.CrossRefPubMed
50.
Pihlaja R, Koistinaho J, Kauppinen R, Sandholm J, Tanila H, Koistinaho M. Multiple cellular and molecular mechanisms are involved in human Aβ clearance by transplanted adult astrocytes. Glia. 2011;59:1643–57.CrossRefPubMed
51.
Malm T, Mariani M, Donovan LJ, Neilson L, Landreth GE. Activation of the nuclear receptor PPAR¿ is neuroprotective in a transgenic mouse model of Alzheimer’s disease through inhibition of inflammation. J Neuroinflammation. 2015;12:7.PubMedCentralCrossRefPubMed
52.
Rolova T, Puli L, Magga J, Dhungana H, Kanninen K, Wojciehowski S, et al. Complex regulation of acute and chronic neuroinflammatory responses in mouse models deficient for nuclear factor kappa B p50 subunit. Neurobiol Dis. 2014;64:16–29.CrossRefPubMed
Metadata
Title
ADAMTS-4 promotes neurodegeneration in a mouse model of amyotrophic lateral sclerosis
Authors
Sighild Lemarchant
Yuriy Pomeshchik
Iurii Kidin
Virve Kärkkäinen
Piia Valonen
Sarka Lehtonen
Gundars Goldsteins
Tarja Malm
Katja Kanninen
Jari Koistinaho
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2016
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/s13024-016-0078-3

Other articles of this Issue 1/2016

Molecular Neurodegeneration 1/2016 Go to the issue

Erratum

Erratum to: Transmission of α-synucleinopathy from olfactory structures deep into the temporal lobe

Research article

Deimmunization for gene therapy: host matching of synthetic zinc finger constructs enables long-term mutant Huntingtin repression in mice

Research article

Pim1 inhibition as a novel therapeutic strategy for Alzheimer’s disease

Methodology

Automated longitudinal monitoring of in vivo protein aggregation in neurodegenerative disease C. elegans models

Methodology

A rapid and cost-effective method for genotyping apolipoprotein E gene polymorphism

Research article

Early-life stress leads to impaired spatial learning and memory in middle-aged ApoE4-TR mice