CENTRAL DEGENERATION OF PRIMARY AFFERENT CONNECTIVITY IN A PRECLINICAL MODEL OF CHARCOT-MARIE-TOOTH DISEASE TYPE 2D

Charcot-Marie-Tooth Disease Type 2D (CMT2D) is an inherited peripheral neuropathy resulting from missense or small in-frame indel mutations in Gars, encoding glycyl-tRNA synthase. Mutations in the Gars gene results in various sensory-motor abnormalities, including the loss of the stretch reflex. This pathway is normally mediated by the activation of stretch-sensitive sensory Ia afferents that innervate muscle spindle and project directly onto motoneurons located in the ventral horn of the spinal cord. Here, we sought to determine whether muscle spindle denervation in a model of CMT2D leads to the central loss of primary afferent connections with motoneurons.We examined how degeneration of sensory afferents alters neural encoding and disrupts sensory-guided movements. Using mice carrying a patient-associated mutation (Gars^DETAQ), we tested proprioception with a behavioral readout, followed by physiological recordings and anatomical evaluation. Retrogradely labeled spinal motor neurons in Gars^DETAQ and littermate controls were reconstructed and synaptic boutons from primary Ia afferents were mapped across the soma and proximal dendrites to compare synaptic densities between the two groups. Muscle spindles were also labeled and quantified. We found a significant depletion in sensory Ia afferents synapses in the soma and proximal dendrite of motoneurons in Gars^DETAQ compared to littermate controls, contributing to poor sensory-motor performance. Findings demonstrate that the Gars^DETAQ mutation disrupts peripheral axon function and leads to central degeneration of monosynaptic Ia afferents projecting to motoneurons, which are essential proprioceptive signaling. Such deficits suggests that sensory control of movement is compromised and that it should be considered in pursuit of therapeutic strategies.