Non-somatic synaptic and axonal compartments of neurons are primary pathological targets in many neurodegenerative conditions, ranging from Alzheimer’s disease through to motor neuron disease. Axons and synapses are protected from degeneration by the slow Wallerian degeneration (Wld^s) gene. Significantly, the molecular mechanisms through which this spontaneous genetic mutation delays degeneration remain controversial and the downstream protein targets of Wld^s resident in non-somatic compartments remain unknown. Here we have used differential proteomic analysis to identify proteins whose expression levels were significantly altered in isolated synaptic preparations from the striatum of Wld^s mice. 8 of the 16 proteins we identified as having modified expression levels in Wld^s synapses are known regulators of mitochondrial stability and degeneration (including VDAC1, Aralar1 and mitofilin). Subsequent analyses demonstrated that other key mitochondrial proteins, not identified in our initial screen, are also modified in Wld^s synapses. Of the non-mitochondrial proteins identified, several have been implicated in neurodegenerative diseases where synapses and axons are primary pathological targets (including DRP-2 and Rab GDI beta). In addition, we show that downstream protein changes can be identified in pathways corresponding to both Ube4b (including Ube1) and Nmnat1 (including VDAC1 and Aralar1) components of the chimeric Wld^s gene, suggesting that full-length Wld^s protein is required to elicit maximal changes in synaptic proteins. We conclude that altered mitochondrial responses to degenerative stimuli are likely to play an important role in the neuroprotective Wld^s phenotype and that targeting proteins identified in the current study may lead to novel therapies for the treatment of neurodegenerative diseases in humans.