The Loss of Proprioception as a Mechanism Underlying the SMA Phenotype

Spinal muscular atrophy (SMA) is a severe motor neuron disease caused by reduced levels of survival motor neuron (SMN) protein caused by deletions in the survival motor neuron 1 (SMN1) gene, the SMA-determining gene, and SMA patients retain at least one copy of the nearly identical SMN2 gene. The SMN2 gene produces low levels of full-length SMN and cannot compensate for the loss of SMN1. Currently, there is no effective treatment, and design of novel therapeutics is hampered by our limited knowledge of the cellular mechanisms involved. Most prior studies have focused on the motor neuron and the neuromuscular junction. However, we recently found that in the widely studied SMA-delta7 mouse model of SMA, one of the earliest detectable phenotypes is a loss of neurotransmission in the reflex circuit formed by proprioceptive afferents on spinal motor neurons. SMA motor neurons show reduced proprioceptive reflexes that correlate with decreased number and function of synapses on motor neuron somata and proximal dendrites. These abnormalities occur at an early stage of disease in motor neurons innervating proximal hindlimb muscles and medial motor neurons innervating axial muscles, but only at end-stage disease in motor neurons innervating distal hindlimb muscles. Motor neuron loss follows afferent synapse loss with the same temporal and topographical pattern. Hence, de-afferentation of motor neurons is an early event in SMA, and we hypothesize that defects in proprioception may play a key role in the progression and even the pathogenesis of SMA and is amenable to therapeutic intervention. In a set of novel experiments, we will investigate the relative contributions of changes in motor neurons and proprioceptive neurons to SMA disease onset and progression.