Neuronal Matrix Metalloproteinase-9 Is a Determinant of Selective Neurodegeneration

•Motor neuron subpopulations show highly divergent patterns of gene expression•Matrix metalloproteinase-9 (MMP-9) is a marker for vulnerable fast motor neurons•Reductions in MMP-9 delay muscle denervation and prolong survival in ALS model mice•MMP-9 enhances ER stress in vulnerable motor neurons and triggers degeneration

SummarySelective 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.