Disease mechanisms in spinal muscular atrophy with respiratory distress type 1 (SMARD1): what about motoneurons?

Abstract

Spinal muscular atrophy with respiratory distress type 1 (SMARD1), described as a fatal motoneuron disorder in children is characterized by α-motoneuron loss. Most of the SMARD1 patients suffer from diaphragmatic palsy leading to permanent ventilation at very early stages of disease. As muscular atrophy is the predominant clinical sign in SMARD1 patients, the question arises whether motoneuron degeneration occurs cell-autonomously. IGHMBP2, the disease causing gene in SMARD1, encodes for a helicase with still unknown function in motoneurons. Studies from a SMARD1 mouse model (Nmd2J mouse) revealed that degeneration of motor axons precedes muscle fiber atrophy in the gastrocnemius muscle aside from a pure myopathy of the diaphragm without affected motor nerve innervation. Nmd2J mice suffer from a reduced IGF1 level which can be compensated by external application of a polyethylene glycol (PEG)-coupled variant of IGF1 (PEG-IGF1). The beneficial effects in striated muscles corresponded to a marked activation of the IGF1 receptor (IGF1R), resulting in enhanced phosphorylation of Akt (protein kinase B) and the ribosomal protein S6 kinase. Unfortunately, no protective effects of PEG-IGF1 were observed at the level of motoneuron survival. Fast motor axon loss innervating the gastrocnemius muscle of Nmd2J mice does not correspond to morphological and functional alterations at the neuromuscular endplate as it is described in mouse models for proximal spinal muscular atrophy (SMA). However, the high capacity for axonal sprouting in Nmd2J mice indicates the functionality of the remaining motoneurons. These observations argue for additional non-cell-autonomous disease mechanisms which do not primarily affect the neuromuscular endplate and in general the functionality of Ighmbp2 deficient motoneurons.