Spinal Muscular Atrophy is a Cell Autonomous Disease of the Motor Neuron.

摘要

The loss of motor neurons is a hallmark of the neuromuscular disease spinal muscular atrophy (SMA); however it is unclear whether this phenotype autonomously originates within the motor neuron. To address this question, we developed an inducible mouse model of severe SMA that has reduced survival and motor function, motor unit pathology and hyper-excitable motor neurons. Using an Hb9-Cre allele, we increased Smn levels autonomously within motor neurons, and demonstrate that motor neuron rescue significantly improves all phenotypes and pathologies commonly described in SMA mice. This represents the first evidence in a mammalian model of SMA that increasing Smn in motor neurons is sufficient to prevent neurodegeneration. Paradoxically, survival is only extended by 5 days in motor neuron rescue SMA mice, due in part to failed autonomic innervation of the myocardium; a defect that we show to be independent of neuromuscular dysfunction. We also establish that motor neuron rescue prevents sensory-motor synaptic stripping, a proposed cellular mechanism underlying SMA motor neuron degeneration. The retention of sensory afferent synapses coincides with the correction of voltage threshold and persistent inward current defects in SMA motor neurons, indicating that hyper-excitability is rescued. Collectively, this work demonstrates that the SMA phenotype autonomously originates in motor neurons and that sensory-motor synapse loss is a consequence, not a cause, of motor neuron dysfunction.