Genetic evaluation of the p53 cell death pathway in spinal muscular atrophy (SMA)

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DESCRIPTION (provided by applicant): The childhood genetic disease spinal muscular atrophy (SMA) leads to progressive muscle weakness and loss of motor neurons in the spinal cord. In all cases this results from reductions in the levels of the ubiquitous SMN (survival of motor neuron protein) and current therapeutic approaches focused on upregulating SMN have shown success in mouse models and will be tested in patients. However, these remain untested strategies and it is not probable that upregulation of SMN in patients that already show symptoms will alone be sufficient to correct all functional deficits. There is therefore a need to better understand the disease mechanism and define new approaches to therapy based on this knowledge. The current vision of SMA is that defects in spinal motor circuits precede degeneration and death of motor neurons but that both contribute to the disease phenotype. Clinically, the most affected motor neurons are those that innervate proximal muscles. We have shown that these medial motor column (MMC) motor neurons are selectively lost in the SMA-Δ7 mouse model. By gene profiling of MMC motor neurons before they degenerate, we identified the tumor suppressor p53 and its downstream effector PERP (p53 apoptosis effector related to PMP-22) as candidate intermediates in the motor neuron death pathway. In support of this hypothesis, administration of an inhibitor of p53 to SMA- Δ7 mice significantly increased weight gain and prevented motor neuron loss. However, the effects are transient and the drug does not correct the pronounced behavioral deficits. To determine whether this incomplete rescue reflects limitations of the drug itself, we propose to evaluate the role of p53 and PERP genetically by crossing SMA mice to conditional knockouts for each, using a novel inducible motor neuron-specific Cre driver. The results will help to define the role of the first cell death pathway deduced by examination of the most vulnerable motor neurons in SMA, and should allow us to determine the contribution of motor neuron cell death to the overall phenotype of the SMA mice. In the future this may lead to the definition of novel therapeutic targets for prevention of motor neuron death in affected patients.