Mechanisms of motor unit pathology in motor neuron diseases

• Applicant: Dr. Christian Simon
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2018 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 408763458

Spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) are incurable motor neuron diseases, which represent a great burden for the affected patients and their families. Motor unit pathology leads to muscle paralysis and eventually to the patient’s death. Initially, retraction of the motor axon from the neuromuscular junction (NMJ) leads to denervation of the muscles, which is followed by the death of motor neuron cell body, suggesting NMJ denervation might induce motor neuron death. However, the mechanisms of NMJ denervation and its correlation to neuronal death are unknown. To decipher the mechanisms of motor unit pathology, we will conduct three work packages, applying novel clearing methods, confocal microscopy and state-of-the-art electrophysiology to mouse models for SMA and ALS. First, we will investigate individually labeled degenerating motor units to determine the correlation between NMJ denervation and motor neuron death. Secondly, we will investigate the contribution of cytoskeleton dynamics to NMJ denervation with the aim to relate it causally to motor neuron death. Thirdly, we will examine the link between NMJ dysfunction and denervation and chronically alter neuronal activity of the motor unit by FDA approved drug application to study the consequences for NMJ innervation and motor neuron survival. Collectively, the proposed experiments will reveal the contribution of cytoskeleton dynamics and neuronal activity on NMJ denervation and a potential causal relationship to motor neuron death. Importantly, testing potentially beneficial drugs could form the basis for future translational work, aimed to improve the quality of life of patients with motor neuron diseases.

• DFG Programme: Research Grants