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

• Final Report Year: 2024

Final Report Abstract

This study investigates the pathophysiology of motor unit degeneration in spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). The focus is on understanding the relationship between neuromuscular junction (NMJ) denervation, motor neuron death, microtubule dynamics and neuronal activity in these diseases. First, we developed a protocol for spinal cord tissue-clearing in combination with established markers to perform automated motor neuron quantification using a freeware, allowing unbiased analysis of motor neuron numbers in intact spinal cord segments. Studies on motor unit vulnerability revealed segmentspecific patterns of NMJ denervation and motor neuron death in ALS and SMA models. In ALS, NMJ denervation was tightly correlated with subsequent motor neuron death, while in SMA, these appeared as independent pathological events. Furthermore, a decrease of stable microtubules in motor axons correlated with NMJ denervation in ALS mice, suggesting that microtubule destabilization is a precursor to motor unit pathology. SMA mice exhibited NMJ dysfunction before denervation, with a significant functional reduction despite partial NMJ innervation. Increase of neuronal activity induced axonal sprouting and NMJ reinnervation but did not prevent motor neuron death, suggesting that enhanced neuronal activity promotes compensation rather than neuroprotection. Overall, our results suggest microtubule stabilization as a promising therapeutic target for ALS. The dissociation between NMJ denervation and motor neuron death in SMA highlights the need for distinct therapeutic approaches targeting these independent mechanisms. One possible approach is the increase of neuronal activity to promote axonal sprouting and NMJ reinnervation in SMA. This research underscores the complex and multifaceted mechanisms underlying motor unit pathology in ALS and SMA, offering insights for targeted therapeutic strategies.

Publications

• Chronic Pharmacological Increase of Neuronal Activity Improves Sensory-Motor Dysfunction in Spinal Muscular Atrophy Mice. The Journal of Neuroscience, 41(2), 376-389.
  Simon, Christian M.; Blanco-Redondo, Beatriz; Buettner, Jannik M.; Pagiazitis, John G.; Fletcher, Emily V.; Sime, Longang Josiane K. & Mentis, George Z.
  
• Central synaptopathy is the most conserved feature of motor circuit pathology across spinal muscular atrophy mouse models. iScience, 24(11), 103376.
  Buettner, Jannik M.; Sime, Longang Josiane K.; Gerstner, Florian; Apel, Katharina S.; Blanco-Redondo, Beatriz; Sowoidnich, Leonie; Janzen, Eva; Langenhan, Tobias; Wirth, Brunhilde & Simon, Christian M.
  
• Laser microscopy acquisition and analysis of premotor synapses in the murine spinal cord. STAR Protocols, 3(1), 101236.
  Buettner, Jannik M.; Kirmann, Toni; Mentis, George Z.; Hallermann, Stefan & Simon, Christian M.
  
• Boosting neuregulin 1 type-III expression hastens SMA motor axon maturation. Acta Neuropathologica Communications, 11(1).
  Kong, Lingling; Hassinan, Cera W.; Gerstner, Florian; Buettner, Jannik M.; Petigrow, Jeffrey B.; Valdivia, David O.; Chan-Cortés, Michelle H.; Mistri, Amy; Cao, Annie; McGaugh, Scott Alan; Denton, Madeline; Brown, Stephen; Ross, Joshua; Schwab, Markus H.; Simon, Christian M. & Sumner, Charlotte J.
  
• Doctoral medical thesis – Pathologische Mechanismen der Sensomotorik in verschiedenen Mausmodellen für spinale Muskelatrophie
  Jannik M. Buettner