Mechanisms of p53-mediated motor neuron death in spinal muscular atrophy

• Applicant: Dr. Christian Simon
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 467567954

Neurodegenerative disorders are caused by the death of selective neuronal populations. However, the mechanisms of ubiquitous expression of mutated genes inducing the death of a distinct group of neurons remain mostly unknown. One of the most frequent neurological disorders in children is the monogenic motor neuron disease spinal muscular atrophy (SMA), in which the deficiency of the ubiquitously expressed SMN protein causes the death of specific spinal motor neuron pools. Recently, we showed that two SMN-dependent distinct events of nuclear accumulation and phosphorylation of p53 converge to trigger selective motor neuron death in a severe SMA mouse model. However, it is neither known whether p53-dependent motor neuron death extends beyond the severe model to include other SMA mouse models and patients nor which p53-downstream effectors execute motor neuron death in SMA.To address these questions of pathophysiological relevance, we will investigate first whether the p53 pathway is commonly activated in vulnerable motor neuron pools across SMA mouse models and human postmortem spinal cord tissue with different disease severities by applying immunohistochemistry and confocal imaging. We will further use established pharmacological and viral approaches to causally link p53 pathway activation to motor neuron death in different SMA mouse models. Finally, we will validate the function of two previously identified p53-downstream effectors in motor neuron death and sensory-motor circuit pathology with molecular biology and electrophysiology. In summary, this research proposal will clarify the general role of the p53 pathway in motor neuron death and identify p53-downstream effectors which could yield novel targets for motor neuron death prevention in SMA and other neurodegenerative disease.

• DFG Programme: Research Grants