Abstract
Synapses represent a major pathological target across a broad range of neurodegenerative conditions. Recent studies addressing molecular mechanisms regulating synaptic vulnerability and degeneration have relied heavily on invertebrate and mouse models. Whether similar molecular neuropathological changes underpin synaptic breakdown in large animal models and in human patients with neurodegenerative disease remains unclear. We therefore investigated whether molecular regulators of synaptic pathophysiology, previously identified in Drosophila and mouse models, are similarly present and modified in the brain of sheep with CLN5 Batten disease. Gross neuropathological analysis of CLN5 Batten disease sheep and controls was used alongside postmortem MRI imaging to identify affected brain regions. Synaptosome preparations were then generated and quantitative fluorescent Western blotting used to determine and compare levels of synaptic proteins. The cortex was particularly affected by regional neurodegeneration and synaptic loss in CLN5 sheep, whilst the cerebellum was relatively spared. Quantitative assessment of the protein content of synaptosome preparations revealed significant changes in levels of seven out of eight synaptic neurodegeneration proteins investigated in the motor cortex, but not cerebellum, of CLN5 sheep (α-synuclein, CSP-α, neurofascin, ROCK2, calretinin, SIRT2, and UBR4). Synaptic pathology is a robust correlate of region-specific neurodegeneration in the brain of CLN5 sheep, driven by molecular pathways similar to those reported in Drosophila and rodent models. Thus, large animal models, such as sheep, represent ideal translational systems to develop and test therapeutics aimed at delaying or halting synaptic pathology for a range of human neurodegenerative conditions.
Highlights
Progressive neurological conditions such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and some lysosomal storage disorders, including the neuronal ceroid lipofuscinoses (NCLs; Batten disease; http:// www.ucl.ac.uk/ncl (Kousi et al 2012)), are a genetically, pathologically and clinically heterogeneous group of diseases
Our initial findings confirmed the regionally restricted nature of disruption to synaptic integrity in areas of the brain of CLN5 sheep undergoing significant neurodegeneration
Previous studies using mouse and Drosophila models of Batten disease have revealed that synaptic disruption is intimately linked to the regional onset of neurodegeneration (Cooper 2010; Bond et al 2013), with our findings demonstrating that the relationship between synaptic pathology and neurodegeneration is likely to be conserved in CLN5 sheep
Summary
Progressive neurological conditions such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and some lysosomal storage disorders, including the neuronal ceroid lipofuscinoses (NCLs; Batten disease; http:// www.ucl.ac.uk/ncl (Kousi et al 2012)), are a genetically, pathologically and clinically heterogeneous group of diseases. Synaptic dysfunction and degeneration is an early event occurring in affected brain regions during many genetically distinct forms of Batten disease (NCL) (Virmani et al 2005; Luiro et al 2006; Partanen et al 2008; Kielar et al 2009; Koch et al 2011). That synaptic pathology represents a common cellular event across numerous neurological disorders raises the possibility of shared molecular mechanisms regulating synaptic pathophysiology that are independent of the neurodegenerative “trigger”. This hypothesis is supported by several lines of experimental evidence. At the molecular level, a number of individual synaptic proteins that can modulate synaptic vulnerability and degeneration in response to a variety of pathological stimuli have recently been identified, including CSP alpha/DNAJC5 (Fernandez-Chacon et al 2004; Garcıa-Junco-Clemente et al 2010; Noskova et al 2011; Wishart et al 2012; Kashyap et al 2014)
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