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Neuron. 2014 Jan 22;81(2):333-48. doi: 10.1016/j.neuron.2013.12.009.

Neuronal matrix metalloproteinase-9 is a determinant of selective neurodegeneration.

Author information

1
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.
2
Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
3
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.
4
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.

Abstract

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.

Comment in

PMID:
24462097
PMCID:
PMC6015650
DOI:
10.1016/j.neuron.2013.12.009
[Indexed for MEDLINE]
Free PMC Article

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