Abstract
BackgroundDisruption of synaptic connectivity is a significant early event in many neurodegenerative conditions affecting the aging CNS, including Alzheimer's disease and Parkinson's disease. Therapeutic approaches that protect synapses from degeneration in the aging brain offer the potential to slow or halt the progression of such conditions. A range of animal models expressing the slow Wallerian Degeneration (WldS) gene show robust neuroprotection of synapses and axons from a wide variety of traumatic and genetic neurodegenerative stimuli in both the central and peripheral nervous systems, raising that possibility that WldS may be useful as a neuroprotective agent in diseases with synaptic pathology. However, previous studies of neuromuscular junctions revealed significant negative effects of increasing age and positive effects of gene-dose on WldS-mediated synaptic protection in the peripheral nervous system, raising doubts as to whether WldS is capable of directly conferring synapse protection in the aging brain.Methodology/Principal FindingsWe examined the influence of age and gene-dose on synaptic protection in the brain of mice expressing the WldS gene using an established cortical lesion model to induce synaptic degeneration in the striatum. Synaptic protection was found to be sensitive to WldS gene-dose, with heterozygous WldS mice showing approximately half the level of protection observed in homozygous WldS mice. Increasing age had no influence on levels of synaptic protection. In contrast to previous findings in the periphery, synapses in the brain of old WldS mice were just as strongly protected as those in young mice.Conclusions/SignificanceOur study demonstrates that WldS-mediated synaptic protection in the CNS occurs independently of age, but is sensitive to gene dose. This suggests that the WldS gene, and in particular its downstream endogenous effector pathways, may be potentially useful therapeutic agents for conferring synaptic protection in the aging brain.
Highlights
Synaptic connections are an early pathological target in many neurodegenerative conditions, ranging from Alzheimer’s disease, prion diseases and Batten disease through to childhood and adult forms of motor neuron disease [1,2,3,4,5,6,7,8]
In this study we examined the influence of gene-dose and increasing age on synaptic protection in the brain of mice expressing the WldS gene
We demonstrate that synaptic protection in the striatum was sensitive to WldS gene-dose following cortical lesion, with heterozygous WldS mice showing approximately half the level of protection observed in homozygous WldS mice
Summary
Synaptic connections are an early pathological target in many neurodegenerative conditions, ranging from Alzheimer’s disease, prion diseases and Batten disease through to childhood and adult forms of motor neuron disease [1,2,3,4,5,6,7,8]. The WldS gene confers strong neuroprotection upon synaptic and axonal compartments of neurons following injury in both the peripheral and central nervous systems [9,10], but has no direct effect on neuronal soma [11] These neuroprotective properties significantly modify disease onset and/or progression in animal models of chemically-induced Parkinson’s disease [12,13], demyelinating neuropathies [14], some forms of motor neuron disease [15] and global cerebral ischemia [16], highlighting the potential use of WldS and/or its downstream mediators to generate novel therapeutic approaches for the treatment of neurological disorders. Previous studies of neuromuscular junctions revealed significant negative effects of increasing age and positive effects of gene-dose on WldS-mediated synaptic protection in the peripheral nervous system, raising doubts as to whether WldS is capable of directly conferring synapse protection in the aging brain
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