Glial activation spreads from specific cerebral foci and precedes neurodegeneration in presymptomatic ovine neuronal ceroid lipofuscinosis (CLN6)

Oswald, Manfred J.; Palmer, David N.; Kay, Graham W.; Shemilt, Stephen J. A.; Rezaie, Payam; Cooper, Jonathan D.

doi:10.1016/j.nbd.2005.01.025

Cited by 103 publications

(148 citation statements)

References 59 publications

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“…After this, the ICV was reduced in both CLN5 − / − and CLN6 − / − animals, while the ICV of control animals plateaued. The 3D reconstructions revealed that the ICV changes follow the regionality of neuropathology that has been previously described (Oswald et al, 2005; Oswald, Palmer, Kay, Barwell, & Cooper, 2008). …”

Section: Discussionsupporting

confidence: 64%

Computed tomography provides enhanced techniques for longitudinal monitoring of progressive intracranial volume loss associated with regional neurodegeneration in ovine neuronal ceroid lipofuscinoses

et al. 2018

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IntroductionThe neuronal ceroid lipofuscinoses (NCLs; Batten disease) are a group of fatal neurodegenerative lysosomal storage diseases of children caused by various mutations in a range of genes. Forms associated with mutations in two of these, CLN5 and CLN6, are being investigated in well‐established sheep models. Brain atrophy leading to psychomotor degeneration is among the defining features, as is regional progressive ossification of the inner cranium. Ongoing viral‐mediated gene therapy trials in these sheep are yielding encouraging results. In vivo assessment of brain atrophy is integral to the longitudinal monitoring of individual animals and provides robust data for translation to treatments for humans.MethodsComputed tomography (CT)‐based three‐dimensional reconstruction of the intracranial volume (ICV) over time reflects the progression of cortical brain atrophy, verifying the use of ICV measurements as a surrogate measure for brain size in ovine NCL.ResultsICVs of NCL‐affected sheep increase for the first few months, but then decline progressively between 5 and 13 months in CLN5−/− sheep and 11–15 months in CLN6−/−sheep. Cerebral ventricular volumes are also increased in affected animals. To facilitate ICV measures, the radiodensities of ovine brain tissue and cerebrospinal fluid were identified. Ovine brain tissue exhibited a Hounsfield unit (HU) range of (24; 56) and cerebrospinal fluid a HU range of (−12; 23).ConclusionsComputed tomography scanning and reconstruction verify that brain atrophy ovine CLN5 NCL originates in the occipital lobes with subsequent propagation throughout the whole cortex and these regional differences are reflected in the ICV loss.

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Section: Discussionsupporting

confidence: 64%

Computed tomography provides enhanced techniques for longitudinal monitoring of progressive intracranial volume loss associated with regional neurodegeneration in ovine neuronal ceroid lipofuscinoses

et al. 2018

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“…Subsequent experiments using cells cultured by the methods here have revealed that this process is more complex, and that there is a glial cell involvement. This mimics the development of pathology in vivo (Oswald et al, 2005). Studies on the interactions of glia and neurons are on-going.…”

Section: Discussionmentioning

confidence: 95%

The development and characterisation of complex ovine neuron cultures from fresh and frozen foetal neurons

Kay

Oswald

Palmer

2006

Journal of Neuroscience Methods

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“…2009), whereas glial activation and neurodegeneration generally begins in the upper cortex in large animal models of Batten disease (best described in CLN6 sheep (Oswald et al. 2005, 2008)) and human Batten disease patients, with the cerebellum remaining largely spared. In contrast, the neuropathological changes we report here suggest similar regional targeting in CLN5 mice (von Schantz et al.…”

Section: Discussionmentioning

confidence: 99%

“…2005). Images were captured using a Nikon Eclipse 50i model microscope and cortical thicknesses in three animals of each genotype at 24 months of age were determined using NIS‐Elements Software (Nikon Instruments Inc., Melville, NY).…”

Section: Methodsmentioning

confidence: 99%

Molecular neuropathology of the synapse in sheep with CLN5 Batten disease

et al. 2015

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AimsSynapses 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.MethodsGross 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.ResultsThe 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).ConclusionsSynaptic 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.

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Glial activation spreads from specific cerebral foci and precedes neurodegeneration in presymptomatic ovine neuronal ceroid lipofuscinosis (CLN6)

Cited by 103 publications

References 59 publications

Computed tomography provides enhanced techniques for longitudinal monitoring of progressive intracranial volume loss associated with regional neurodegeneration in ovine neuronal ceroid lipofuscinoses

Computed tomography provides enhanced techniques for longitudinal monitoring of progressive intracranial volume loss associated with regional neurodegeneration in ovine neuronal ceroid lipofuscinoses

The development and characterisation of complex ovine neuron cultures from fresh and frozen foetal neurons

Molecular neuropathology of the synapse in sheep with CLN5 Batten disease

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