Motor neurons degenerate by p53-mediated apoptosis in a mouse model for a juvenile-onset disease

• Marie Luise Stephan

  Carl Ludwig Institute of Physiology, Faculty of Medicine, University Leipzig

  “Motor neurons degenerate by p53-mediated apoptosis in a mouse model for a juvenile-onset motor neuron disease”
  
  24th September 2024, 11:20
  BBZ Seminar room
  Deutscher Platz 5, 04103 Leipzig

Abstract:

Motor neuron death is a major hallmark of motor neuron diseases. To decipher the molecular mechanisms driving neuronal death is the first step towards development of therapeutics. We investigate here the mechanism of motor neuron death in a mouse model for a juvenile-onset motor neuron disease using confocal imaging, genetic mouse models and viral gene expression. First, we identify a correlated p53 expression in vulnerable motor neurons of mutant mice. Next, we used mutant mice lacking p53 in motor neurons to establish that p53 drives motor neuron death. To identify whether motor neurons die through p53-dependent apoptosis, we investigated the expression of key apoptotic factors. Strikingly, we found a selective upregulation of pro-apoptotic proteins such as y-H2AX, pATM, cytochrome c and caspases in vulnerable motor neurons prior to their death. Logically, overexpression of the anti-apoptotic protein Bcl-XL rescues motor neurons in the investigated mouse model, demonstrating that p53-dependent apoptosis drives motor neuron death. Lastly, we identify hallmark markers of apoptosis in post-mortem tissue of a patient with a juvenile-onset motor neuron disease. Our findings suggest that interference of a p53-dependent apoptotic pathway could be used to prevent or slow down motor neuron death in patients suffering from motor neuron diseases.