title: Molecular neuropathology of the synapse in sheep with CLN5 Batten disease.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Centre for Integrative Physiology University of Edinburgh Hugh Robson Building Edinburgh UK ; Euan MacDonald Centre for Motor Neurone Disease Research University of Edinburgh Hugh Robson Building Edinburgh UK.
authors.forename: Inês S
authors.initials: IS
authors.lastname: Amorim
authors.affiliation: Department of Molecular Biosciences Faculty of Agricultural and Life Sciences and Batten Animal Research Network Lincoln University Christchurch New Zealand.
authors.forename: Nadia L
authors.initials: NL
authors.lastname: Mitchell
authors.affiliation: Department of Molecular Biosciences Faculty of Agricultural and Life Sciences and Batten Animal Research Network Lincoln University Christchurch New Zealand.
authors.forename: David N
authors.initials: DN
authors.lastname: Palmer
authors.affiliation: Department of Physiology, Development and Neuroscience University of Cambridge Downing Street Cambridge UK ; Wolfson Brain Imaging Centre University of Cambridge Box 65 Addenbrooke's Hospital Hills Road Cambridge UK.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Sawiak
authors.affiliation: Department of Physiology, Development and Neuroscience University of Cambridge Downing Street Cambridge UK.
authors.forename: Roger
authors.initials: R
authors.lastname: Mason
authors.affiliation: Euan MacDonald Centre for Motor Neurone Disease Research University of Edinburgh Hugh Robson Building Edinburgh UK ; Division of Neurobiology The Roslin Institute and Royal (Dick) School of Veterinary Studies University of Edinburgh Edinburgh UK.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Wishart
authors.affiliation: Centre for Integrative Physiology University of Edinburgh Hugh Robson Building Edinburgh UK ; Euan MacDonald Centre for Motor Neurone Disease Research University of Edinburgh Hugh Robson Building Edinburgh UK.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Gillingwater
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000473:pathology; D002540:Cerebral Cortex / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D009472:Neuronal Ceroid-Lipofuscinoses / Q000473:pathology*; D012756:Sheep; D012757:Sheep Diseases / Q000473:pathology*; D013569:Synapses / Q000473:pathology*
keywords: Animal model; lysosomal storage disorders; neurodegeneration; neuronal ceroid lipofuscinoses; neuronal ceroid lipofuscinosis; sheep; synapse; synaptic vulnerability