Molecular Mechanisms Underlying Sensory-Motor Circuit Dysfunction in SMA

Abstract

Activation of skeletal muscle in response to acetylcholine release from the neuromuscular junction triggered by motor neuron firing forms the basis of all mammalian locomotion. Intricate feedback and control mechanisms, both from within the central nervous system and from sensory organs in the periphery, provide essential inputs that regulate and finetune motor neuron activity. Interestingly, in motor neuron diseases, such as spinal muscular atrophy (SMA), pathological studies in patients have identified alterations in multiple parts of the sensory-motor system. This has stimulated significant research efforts across a range of different animal models of SMA in order to understand these defects and their contribution to disease pathogenesis. Several recent studies have demonstrated that defects in sensory components of the sensory-motor system contribute to dysfunction of motor neurons early in the pathogenic process. In this review, we provide an overview of these findings, with a specific focus on studies that have provided mechanistic insights into the molecular processes that underlie dysfunction of the sensory-motor system in SMA. These findings highlight the role that cell types other than motor neurons play in SMA pathogenesis, and reinforce the need for therapeutic interventions that target and rescue the wide array of defects that occur in SMA.

Keywords: SMN; motor neuron; neurodegenaration; proprioception; sensory-motor circuit; spinal muscular atrophy.

FIGURE 1

Overview of the sensory-motor system and pathologies observed in SMA. Schematic (A) and immunohistochemical (B) representation of the sensory-motor system, focusing on structures, cell types, and subcellular compartments that have been implicated in SMA pathogenesis. In (A), the text in green indicates the primary pathological changes occurring in specific cell types or in specific subcellular compartments. In (B), immunofluorescence was used to label parvalbumin-expressing cells and projections (proprioceptive neurons; red), neuronal cell bodies (ChAT for motor neurons, beta-III-tubulin for DRG cell bodies; green), and nuclei (DAPI; blue). Note that only a subgroup of DRG cell bodies express parvalbumin and that other markers such as NF200⁺ (mechano- and proprioceptive) and peripherin⁺ (nociceptive) can also be used to identify other types of sensory neurons. Scale bars: 100 μm (spinal cord and DRG); 20 μm (motor neuron). DRG, dorsal root ganglion; ChAT, acetylcholine transferase; DAPI, 4,6-diamidino-2-phenylindole; vGlut1, vesicular glutamate transporter 1; NF200, neurofilament heavy polypeptide (200 kDa).