Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by motor neuron loss and skeletal muscle atrophy. SMA is caused by ubiquitous deficiency in the SMN protein and is the leading genetic cause of infant mortality. To date, most SMA therapeutic approaches have focused on increasing SMN expression and SMN-inducing therapies have recently been approved for SMA. However, these therapies alone do not provide a cure or SMA nd not all patients respond to treatment. Therefore, it remains essential to understand the underlying mechanisms of SMA and identify SMN-independent therapeutic approaches that can enhance the benefit of SMN-inducing strategies through combinatorial treatment. In this context, motor neuron death is an irreversible pathogenic hallmark of SMA. Therefore, preventing motor neuron degeneration has fundamental clinical implications for SMA therapy and could extend the window of opportunity for SMN-inducing therapies to exert their effect. However, this is hindered by limited knowledge of the death pathway and availability of druggable-targets for halting this process. This project aims to address these outstanding issues by investigating the mechanisms underlying the initiation and execution of motor neuron degeneration in SMA as well as validate the therapeutic potential of pharmacologically targeting this pathway in mouse models of the disease. The premise of our proposed work is that the neurodegenerative pathway of SMA motor neurons represents a target- rich domain for the discovery of disease-modifying pharmacological approaches that are SMN-independent and suited for combinatorial treatment of SMA. Building on our published and preliminary studies, we will characterize the upstream mechanisms driving motor neuron death in SMA based on our hypothesis that SMN deficiency triggers a p38MAPK/p53-dependent neurodegenerative pathway (Aim 1). To broaden the range of candidate targets for developing SMN-independent neuroprotective approaches for SMA, we will determine the execution mechanisms of motor neuron death through the identification and functional characterization of the downstream effectors of p53-dependent neurodegeneration in SMA (Aim 2). Lastly, we will leverage on the availability of a highly selective, brain permeable inhibitor to test the hypothesis that p38MAPK activation is a shared pathogenic mechanism associated with motor neuron death across mouse models of SMA with varying disease severity whose inhibition is a viable therapeutic approach (Aim 3). We will also evaluate whether pharmacological inhibition of p38MAPK enables enhanced synaptic rewiring by preserving SMA motor neurons in a paradigm of combinatorial treatment with SMN upregulation. Successful accomplishment of our objectives has the potential to provide key insights into the mechanisms of motor neuron death in SMA, identify new disease markers and candidate targets to hal...