Motor pool selectivity of neuromuscular degeneration in type I spinal muscular atrophy is conserved between human and mouse.

Abstract

Spinal muscular atrophy (SMA) is caused by low levels of the survival motor neuron (SMN) protein. Even though SMN is ubiquitously expressed, the disease selectively affects motor neurons, leading to progressive muscle weakness. Even among motor neurons, certain motor units appear more clinically resistant to SMA. To quantitatively survey selective resistance, we studied extensive neuromuscular autopsies of Type I SMA patients and age-matched controls. We found highly divergent degrees of degeneration of neighboring motor units, even within individual cranial nerves or a single anatomical area such as the neck. Examination of a Type I SMA patient maintained on life support for 17 years found that most muscles were atrophied, but the diaphragm was strikingly preserved. Nevertheless, some resistant human muscles with preserved morphology displayed nearly complete conversion to slow Type I myofibers. Remarkably, a similar pattern of selective resistance was observed in the SMNΔ7 mouse model. Overall, differential motor unit vulnerability in human Type I SMA suggests the existence of potent, motor unit-specific disease modifiers. Mechanisms that confer selective resistance to SMA may represent therapeutic targets independent of the SMN protein, particularly in patients with neuromuscular weakness refractory to current treatments.