Fast motor axon loss in SMARD1 does not correspond to morphological and functional alterations of the NMJ

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a childhood motoneuron disease caused by mutations in the gene encoding for IGHMBP2, an ATPase/Helicase. Paralysis of the diaphragm is an early and prominent clinical sign resulting both from denervation and myopathy. In skeletal muscles, muscle atrophy mainly results from loss of motoneuron cell bodies and axonal degeneration. Although it is well known that loss of motoneurons at the lumbar spinal cord is an early event in the pathogenesis of the disease, it is not clear whether the corresponding proximal axons and NMJs are also early affected. In order to address this question, we have investigated the time course of the disease progression at the level of the motoneuron cell body, proximal axon (ventral root), distal axon (sciatic nerve), NMJ, and muscle fiber in Nmd2J mice, a mouse model for SMARD1. Our results show an early and apparently parallel loss of motoneurons, proximal axons, and NMJs. In affected muscles, however, denervated fibers coexist with NMJs with normal morphology and unaltered neurotransmission. Furthermore, unaffected axons are able to sprout and reinnervate muscle fibers, suggesting selective vulnerability of neurons to Ighmbp2 deficiency. The preservation of the NMJ morphology and neurotransmission in the Nmd2J mouse until motor axon loss takes place, differs from that observed in SMA mouse models in which NMJ impairment is an early and more general phenomenon in affected muscles.

► Pathological changes in the Nmd2J mouse differ from SMA mouse models. ► Proximal and distal motor axon loss in the Nmd2J mouse occurs simultaneously. ► Motor axon loss does not correspond to neurotransmission defects. ► Neurotransmission is not affected as long as the NMJs are intact. ► Axonal sprouting and reinnervation are compensatory mechanisms in the Nmd2J mouse.