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-7 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- 7 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.

Public Health Relevance

Children with the genetic disease spinal muscular atrophy (SMA) exhibit muscle weakness that is often fatal. This reflects the loss of motor neurons - the nerve cells that are required for limb movement and breathing - in the spinal cord of these patients. We have identified a candidate molecular pathway that may explain this loss and now propose to inactivate the pathway in SMA model mice and determine whether it improves their strength and prolongs their lifespan.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Nuckolls, Glen H
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Columbia University (N.Y.)
Schools of Medicine
New York
United States
Zip Code
Fletcher, Emily V; Simon, Christian M; Pagiazitis, John G et al. (2017) Reduced sensory synaptic excitation impairs motor neuron function via Kv2.1 in spinal muscular atrophy. Nat Neurosci 20:905-916
Simon, Christian M; Dai, Ya; Van Alstyne, Meaghan et al. (2017) Converging Mechanisms of p53 Activation Drive Motor Neuron Degeneration in Spinal Muscular Atrophy. Cell Rep 21:3767-3780
Simon, Christian M; Janas, Anna M; Lotti, Francesco et al. (2016) A Stem Cell Model of the Motor Circuit Uncouples Motor Neuron Death from Hyperexcitability Induced by SMN Deficiency. Cell Rep 16:1416-1430