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Molecular & Cellular Proteomics 6:1318-1330, 2007.
© 2007 by The American Society for Biochemistry and Molecular Biology, Inc.

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Research

Differential Proteomics Analysis of Synaptic Proteins Identifies Potential Cellular Targets and Protein Mediators of Synaptic Neuroprotection Conferred by the Slow Wallerian Degeneration (Wld^s) Gene^*,S

Thomas M. Wishart^,, Janet M. Paterson, Duncan M. Short^¶, Sara Meredith, Kevin A. Robertson^||, Calum Sutherland^**, Michael A. Cousin^,, Mayank B. Dutia and Thomas H. Gillingwater^,,

From the Centres for Integrative Physiology and Neuroscience Research, University of Edinburgh Medical School, Edinburgh EH8 9XD, United Kingdom, ^¶ Astellas CNS Research in Edinburgh and ^|| Division of Pathway Medicine, University of Edinburgh, The Chancellor's Building, New Royal Infirmary, Little France Crescent, Edinburgh EH16 4SB, United Kingdom, and ^** Pathology and Neurosciences, University of Dundee, Dundee DD1 9SY, United Kingdom

Non-somatic synaptic and axonal compartments of neurons are primary pathological targets in many neurodegenerative conditions, ranging from Alzheimer 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. In this study we used differential proteomics analysis to identify proteins whose expression levels were significantly altered in isolated synaptic preparations from the striatum of Wld^s mice. Eight 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 GDP dissociation inhibitor ß). 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.

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