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.
Center for Motor Neuron Biology and Disease, Columbia University Medical Center, New York, NY 10032, USA; Departments of Rehabilitation and Regenerative Medicine, Pathology and Cell Biology, Neurology, and Neuroscience, Columbia Stem Cell Initiative, and Columbia Translational Neuroscience Initiative, Columbia University, New York, NY 10032, USA.
Artem
A
Kaplan
Center for Motor Neuron Biology and Disease, Columbia University Medical Center, New York, NY 10032, USA; Departments of Rehabilitation and Regenerative Medicine, Pathology and Cell Biology, Neurology, and Neuroscience, Columbia Stem Cell Initiative, and Columbia Translational Neuroscience Initiative, Columbia University, New York, NY 10032, USA.
Krista J
KJ
Spiller
Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
Christopher
C
Towne
Center for Motor Neuron Biology and Disease, Columbia University Medical Center, New York, NY 10032, USA; Departments of Rehabilitation and Regenerative Medicine, Pathology and Cell Biology, Neurology, and Neuroscience, Columbia Stem Cell Initiative, and Columbia Translational Neuroscience Initiative, Columbia University, New York, NY 10032, USA.
Kevin C
KC
Kanning
Center for Motor Neuron Biology and Disease, Columbia University Medical Center, New York, NY 10032, USA; Departments of Rehabilitation and Regenerative Medicine, Pathology and Cell Biology, Neurology, and Neuroscience, Columbia Stem Cell Initiative, and Columbia Translational Neuroscience Initiative, Columbia University, New York, NY 10032, USA.
Ginn T
GT
Choe
Center for Motor Neuron Biology and Disease, Columbia University Medical Center, New York, NY 10032, USA; Departments of Rehabilitation and Regenerative Medicine, Pathology and Cell Biology, Neurology, and Neuroscience, Columbia Stem Cell Initiative, and Columbia Translational Neuroscience Initiative, Columbia University, New York, NY 10032, USA.
Adam
A
Geber
Center for Motor Neuron Biology and Disease, Columbia University Medical Center, New York, NY 10032, USA; Department of Neurological Surgery, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Turgay
T
Akay
Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
Patrick
P
Aebischer
Center for Motor Neuron Biology and Disease, Columbia University Medical Center, New York, NY 10032, USA; Departments of Rehabilitation and Regenerative Medicine, Pathology and Cell Biology, Neurology, and Neuroscience, Columbia Stem Cell Initiative, and Columbia Translational Neuroscience Initiative, Columbia University, New York, NY 10032, USA. Electronic address: ch2331@columbia.edu.
Christopher E
CE
Henderson
D000200:Action Potentials / Q000235:genetics / Q000502:physiology; D000367:Age Factors; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002772:Cholera Toxin / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism*; D009121:Muscle Denervation; D018482:Muscle, Skeletal / Q000473:pathology / Q000503:physiopathology; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000473:pathology; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism; D050494:Vesicular Acetylcholine Transport Proteins / Q000378:metabolism
D004268:DNA-Binding Proteins; C103652:Elf2 protein, mouse; C493460:Slc18a3 protein, mouse; D014157:Transcription Factors; D050494:Vesicular Acetylcholine Transport Proteins; D002772:Cholera Toxin; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D010751:Phosphopyruvate Hydratase