Neuronal matrix metalloproteinase-9 is a determinant of selective neurodegeneration

Artem Kaplan; Krista J Spiller; Christopher Towne; Kevin C Kanning; Ginn T Choe; Adam Geber; Turgay Akay; Patrick Aebischer; Christopher E Henderson

doi:10.1016/j.neuron.2013.12.009

Neuronal matrix metalloproteinase-9 is a determinant of selective neurodegeneration

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

Authors

Artem Kaplan¹, Krista J Spiller¹, Christopher Towne², Kevin C Kanning¹, Ginn T Choe¹, Adam Geber¹, Turgay Akay³, Patrick Aebischer², Christopher E Henderson⁴

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Action Potentials / genetics
Action Potentials / physiology
Age Factors
Amyotrophic Lateral Sclerosis / genetics
Amyotrophic Lateral Sclerosis / metabolism
Animals
Cholera Toxin / metabolism
DNA-Binding Proteins / metabolism
Dependovirus / genetics
Disease Models, Animal
Gene Expression Regulation / genetics
Matrix Metalloproteinase 9 / deficiency
Matrix Metalloproteinase 9 / metabolism*
Mice
Mice, Inbred C57BL
Mice, Transgenic
Motor Neurons / metabolism*
Muscle Denervation
Muscle, Skeletal / pathology
Muscle, Skeletal / physiopathology
Neurodegenerative Diseases / genetics*
Neurodegenerative Diseases / pathology
Phosphopyruvate Hydratase / metabolism
Superoxide Dismutase / genetics
Transcription Factors / metabolism
Vesicular Acetylcholine Transport Proteins / metabolism

Substances

DNA-Binding Proteins
Elf2 protein, mouse
Slc18a3 protein, mouse
Transcription Factors
Vesicular Acetylcholine Transport Proteins
Cholera Toxin
SOD1 G93A protein
Superoxide Dismutase
Matrix Metalloproteinase 9
Mmp9 protein, mouse
Phosphopyruvate Hydratase

Associated data

GEO/GSE52118

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding