Abstract
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 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.
Highlights
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
Distal neuronal compartments such as synapses and axons are regarded as primary pathological targets in a broad spectrum of human and animal neurodegenerative conditions, ranging from Alzheimer disease through prion disease to motor neuron disease [2]
Notable potential interactions identified by this analysis included those between voltage-dependent anion-selective channel protein 1 (VDAC1) and Bax (e.g. Bax binds to VDAC1, accelerating channel opening and outflow of cytochrome c from mitochondria [31]) and between ubiquitin-activating enzyme E1 (UBE1) and Jun (e.g. UBE1 is necessary for the degradation of Jun in G0/S phase transition fibroblasts [32])
Summary
Slow Wallerian degeneration; Aralar, calcium-binding mitochondrial carrier protein 1; DRP-2, dihydropyrimidinase-related protein 2; NAD, nicotinamide adenine dinucleotide; Nmnat, nicotinamide mononucleotide adenylyltransferase 1; STI1, stress-induced phosphoprotein 1; UBE1, ubiquitinactivating enzyme E1; VCP, valosin-containing protein; VDAC, voltagedependent anion-selective channel protein; ANOVA, analysis of variance; SNAP, soluble N-ethylmaleimide-sensitive factor attachment protein; GDI, GDP dissociation inhibitor; 2D, two-dimensional; BisTris, 2-[bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)propane-1,3diol; IPA, Ingenuity Pathways Analysis; S, soluble; M, membrane; CAPZ ␣2, F-actin capping protein ␣-2 subunit. We showed that several protein changes identified in Wlds synapses are likely to result in altered mitochondrial responses to neurodegenerative stimuli
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
