Exploring Abnormal Neurofilament Aggregates at the Neuromuscular Junction of a Charcot-Marie- Tooth Disease Type 2E Mouse Model

Charcot-Marie-Tooth Disease (CMT) type 2 is a rare inherited neuropathy that results in the degeneration of peripheral nerves caused by mutations in genes that affect the peripheral axon. CMT patients suffer from sensorimotor problems, such as gait anomaly, reduced tendon reflexes, and leg weakness. Previous studies have reported neurofilament aggregates in the spinal cord and dorsal root ganglia (DRG) of a CMT disease type 2E (CMT2E) mouse model, which is caused by mutations in neurofilament light chain (NEFL) and results in a severe form of CMT. Moreover, transfected human motor neurons have shown abnormal neuronal intermediate filament networks associated with defects in axonal transport; however, the neuromuscular junction (NMJ) remains to be assessed. In the present study, we report abnormal NMJ morphologies with presynaptic varicosities at the NMJ of Nefl N98S/+ mice using high resolution light microscopy. Additionally, wire hang tests revealed reduced grip strength in mutant mice, while electromyography (EMG) measurements showed decreased nerve conduction velocities. Together, these observations shed light on plausible pathomechanisms affecting the NMJ in CMT2E, highlighting abnormalities in synaptic ultrastructure and aggregations that could impact synaptic functionality.