Neuronal Matrix Metalloproteinase-9 Is a Determinant of Selective Neurodegeneration

Selective neuronal loss is the hallmark of neurodegenerative diseases. In patients with amyotrophic lateral sclerosis (ALS), most motor neurons die but those innervating extraocular, pelvic sphincter, and slow limb muscles exhibit selective resistance. We identified 18 genes that show >10-fold differential expression between resistant and vulnerable motor neurons. One of these, matrix metalloproteinase-9 (MMP-9), is expressed only by fast motor neurons, which are selectively vulnerable. In ALS model mice expressing mutant superoxide dismutase (SOD1), reduction of MMP-9 function using gene ablation, viral gene therapy, or pharmacological inhibition significantly delayed muscle denervation. In the presence of mutant SOD1, MMP-9 expressed by fast motor neurons themselves enhances activation of ER stress and is sufficient to trigger axonal die-back. These findings define MMP-9 as a candidate therapeutic target for ALS. The molecular basis of neuronal diversity thus provides significant insights into mechanisms of selective vulnerability to neurodegeneration.

[1]  R. Dwek,et al.  The Hemopexin and O-Glycosylated Domains Tune Gelatinase B/MMP-9 Bioavailability via Inhibition and Binding to Cargo Receptors* , 2006, Journal of Biological Chemistry.

[2]  P. Caroni,et al.  A role for motoneuron subtype–selective ER stress in disease manifestations of FALS mice , 2009, Nature Neuroscience.

[3]  S. Lorenzl,et al.  The matrix metalloproteinases inhibitor Ro 26-2853 extends survival in transgenic ALS mice , 2006, Experimental Neurology.

[4]  K. Talbot,et al.  Transgenics, toxicity and therapeutics in rodent models of mutant SOD1-mediated familial ALS , 2008, Progress in Neurobiology.

[5]  Jochen Roeper,et al.  Individual dopamine midbrain neurons: Functional diversity and flexibility in health and disease , 2008, Brain Research Reviews.

[6]  S. Lorenzl,et al.  The matrix metalloproteinases inhibitor Ro 28-2653 [correction of Ro 26-2853] extends survival in transgenic ALS mice. , 2006, Experimental neurology.

[7]  S. Lorenzl,et al.  Tissue inhibitors of matrix metalloproteinases are elevated in cerebrospinal fluid of neurodegenerative diseases , 2003, Journal of the Neurological Sciences.

[8]  R. Samulski,et al.  Comparison of adeno-associated viral vector serotypes for spinal cord and motor neuron gene delivery. , 2011, Human gene therapy.

[9]  A. Graybiel,et al.  The substantia nigra of the human brain. II. Patterns of loss of dopamine-containing neurons in Parkinson's disease. , 1999, Brain : a journal of neurology.

[10]  V. La Bella,et al.  The role of calcium‐binding proteins in selective motoneuron vulnerability in amyotrophic lateral sclerosis , 1994, Annals of neurology.

[11]  A. Graybiel,et al.  The substantia nigra of the human brain. I. Nigrosomes and the nigral matrix, a compartmental organization based on calbindin D(28K) immunohistochemistry. , 1999, Brain : a journal of neurology.

[12]  E. Martin,et al.  The Transcription Factor Orthodenticle Homeobox 2 Influences Axonal Projections and Vulnerability of Midbrain Dopaminergic Neurons. , 2010 .

[13]  C. Bories,et al.  Early electrophysiological abnormalities in lumbar motoneurons in a transgenic mouse model of amyotrophic lateral sclerosis , 2007 .

[14]  O. Isacson,et al.  Global gene expression profiling of somatic motor neuron populations with different vulnerability identify molecules and pathways of degeneration and protection. , 2010, Brain : a journal of neurology.

[15]  N. Shneider,et al.  Gamma motor neurons express distinct genetic markers at birth and require muscle spindle-derived GDNF for postnatal survival , 2009, Neural Development.

[16]  P. E. Van den Steen,et al.  Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9): The next decade , 2013, Critical reviews in biochemistry and molecular biology.

[17]  Pico Caroni,et al.  Selective Neuronal Vulnerability in Neurodegenerative Diseases: from Stressor Thresholds to Degeneration , 2011, Neuron.

[18]  G. Eichele,et al.  Identification of novel spinal cholinergic genetic subtypes disclose Chodl and Pitx2 as markers for fast motor neurons and partition cells , 2010, The Journal of comparative neurology.

[19]  J. Glass,et al.  Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man , 2004, Experimental Neurology.

[20]  P. Caroni,et al.  Neuroprotection through Excitability and mTOR Required in ALS Motoneurons to Delay Disease and Extend Survival , 2013, Neuron.

[21]  S. Przedborski Molecular targets for neuroprotection , 2004, Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases.

[22]  K. Nagashima,et al.  Preservation of a certain motoneurone group of the sacral cord in amyotrophic lateral sclerosis: its clinical significance. , 1977, Journal of neurology, neurosurgery, and psychiatry.

[23]  J. Sanes,et al.  Shared Resistance to Aging and ALS in Neuromuscular Junctions of Specific Muscles , 2012, PloS one.

[24]  W. Robberecht,et al.  Role of matrix metalloproteinase-9 in a mouse model for amyotrophic lateral sclerosis , 2005, Neuroreport.

[25]  Neil D. Lawrence,et al.  Unravelling the enigma of selective vulnerability in neurodegeneration: motor neurons resistant to degeneration in ALS show distinct gene expression characteristics and decreased susceptibility to excitotoxicity , 2012, Acta Neuropathologica.

[26]  C. Henderson,et al.  Motor neuron diversity in development and disease. , 2010, Annual review of neuroscience.

[27]  K. Abe,et al.  Parvalbumin and calbindin D-28k immunoreactivity in transgenic mice with a G93A mutant SOD1 gene , 2006, Brain Research.

[28]  A Hirano,et al.  Sparing of the onufrowicz nucleus in sacral anterior horn lesions , 1978, Annals of neurology.

[29]  Ran An,et al.  Association Studies of MMP-9 in Parkinson’s Disease and Amyotrophic Lateral Sclerosis , 2013, PloS one.

[30]  P. Aebischer,et al.  Neuroprotection by gene therapy targeting mutant SOD1 in individual pools of motor neurons does not translate into therapeutic benefit in fALS mice. , 2011, Molecular therapy : the journal of the American Society of Gene Therapy.

[31]  F. Fornai,et al.  A systematic study of brainstem motor nuclei in a mouse model of ALS, the effects of lithium , 2010, Neurobiology of Disease.

[32]  Zuoshang Xu,et al.  Allele-specific RNAi selectively silences mutant SOD1 and achieves significant therapeutic benefit in vivo , 2006, Neurobiology of Disease.

[33]  J. Lipski,et al.  Calcium binding proteins in motoneurons at low and high risk for degeneration in ALS , 2000, NeuroReport.

[34]  P. Caroni,et al.  Early and Selective Loss of Neuromuscular Synapse Subtypes with Low Sprouting Competence in Motoneuron Diseases , 2000, The Journal of Neuroscience.

[35]  T. Nakajima,et al.  MMP-13 plays a role in keratinocyte migration, angiogenesis, and contraction in mouse skin wound healing. , 2009, The American journal of pathology.

[36]  E. Aronica,et al.  Immunohistochemical localization of group I and II metabotropic glutamate receptors in control and amyotrophic lateral sclerosis human spinal cord: upregulation in reactive astrocytes , 2001, Neuroscience.

[37]  Q. Zhu,et al.  Protective effect of neurofilament heavy gene overexpression in motor neuron disease induced by mutant superoxide dismutase. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[38]  P. Aebischer,et al.  Systemic AAV6 delivery mediating RNA interference against SOD1: neuromuscular transduction does not alter disease progression in fALS mice. , 2008, Molecular therapy : the journal of the American Society of Gene Therapy.

[39]  E. Reske‐Nielsen,et al.  Preservation of the nucleus X-pelvic floor motosystem in amyotrophic lateral sclerosis. , 1984, Clinical neuropathology.

[40]  Pico Caroni,et al.  Selective vulnerability and pruning of phasic motoneuron axons in motoneuron disease alleviated by CNTF , 2006, Nature Neuroscience.

[41]  Gabriele Bergers,et al.  MMP-9/Gelatinase B Is a Key Regulator of Growth Plate Angiogenesis and Apoptosis of Hypertrophic Chondrocytes , 1998, Cell.

[42]  Alcino J. Silva,et al.  Matrix Metalloproteinase-9 Is Required for Hippocampal Late-Phase Long-Term Potentiation and Memory , 2006, The Journal of Neuroscience.

[43]  Silvia Arber,et al.  Gamma and alpha motor neurons distinguished by expression of transcription factor Err3 , 2009, Proceedings of the National Academy of Sciences.

[44]  D. Cleveland,et al.  Non–cell autonomous toxicity in neurodegenerative disorders: ALS and beyond , 2009, The Journal of cell biology.

[45]  T. Gordon,et al.  Time course of preferential motor unit loss in the SOD1G93A mouse model of amyotrophic lateral sclerosis , 2007, Neurobiology of Disease.

[46]  A. Krüger,et al.  Avoiding spam in the proteolytic internet: future strategies for anti-metastatic MMP inhibition. , 2010, Biochimica et biophysica acta.

[47]  S. Rafii,et al.  Matrix metalloproteinase-9 regulates TNF-α and FasL expression in neuronal, glial cells and its absence extends life in a transgenic mouse model of amyotrophic lateral sclerosis , 2007, Experimental Neurology.

[48]  Jeffrey D. Rothstein,et al.  From charcot to lou gehrig: deciphering selective motor neuron death in als , 2001, Nature Reviews Neuroscience.

[49]  A. Goris,et al.  EPHA4 is a disease modifier of amyotrophic lateral sclerosis in animal models and in humans , 2012, Nature Medicine.

[50]  S. Swarnakar,et al.  The gelatinases and their inhibitors: the structure-activity relationships. , 2012, Experientia supplementum.

[51]  R. Burke,et al.  Membrane area and dendritic structure in type‐identified triceps surae alpha motoneurons , 1987, The Journal of comparative neurology.