Use of model organisms for the study of neuronal ceroid lipofuscinosis

Bond, Michael; Holthaus, Sophia-Martha kleine; Tammen, Imke; Tear, Guy; Russell, Claire

doi:10.1016/j.bbadis.2013.01.009

Cited by 84 publications

(76 citation statements)

References 313 publications

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“…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 similarly conserved in CLN5 sheep. However, given the symptomatic nature of the sheep investigated in this study, further studies examining synaptic changes at pre and early‐symptomatic time points will now be required in order to establish whether synaptic loss precedes, or occurs concurrently with, gross neuropathological changes.…”

Section: Discussionsupporting

confidence: 73%

“…2011; Bond et al. 2013). Batten disease often refers to a group of fatal neurodegenerative disorders that mainly begin in childhood, representing the most common group of childhood neurodegenerative diseases, also collectively known as the neuronal ceroid lipofuscinoses (NCLs) (Palmer et al.…”

Section: Introductionmentioning

confidence: 99%

“…2011; Bond et al. 2013). The sheep used in this study have a late infantile variant CLN5 form of Batten disease.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 73%

Section: Introductionmentioning

confidence: 99%

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Molecular neuropathology of the synapse in sheep with CLN5 Batten disease

et al. 2015

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“…As no one has yet demonstrated overt seizures or retinal degeneration in the mouse model [21], this zebrafish model is potentially more relevant to the disease than the mouse model.…”

Section: Cln2 Diseasementioning

confidence: 99%

“…Compared to disease onset at 7 weeks in the mouse model [21], the embryonic onset and fast progression in the zebrafish model offers the potential to complete experiments much more quickly.…”

Section: Cln2 Diseasementioning

confidence: 99%

New Zebrafish Models of Neurodegeneration

Martín-Jiménez

Campanella

Russell

2015

Curr Neurol Neurosci Rep

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In modern biomedicine the increasing need to develop experimental models to further our understanding of disease conditions and delineate innovative treatments has found in the zebrafish (Danio rerio) an experimental model, and indeed a valuable asset, to close the gap between in vitro and in vivo assays. Translation of ideas at a faster pace is vital in the field of neurodegeneration, with the attempt to slow or prevent the dramatic impact on society's welfare being an essential priority. Our research group has pioneered the use of zebrafish to contribute to the quest for faster and improved understanding and treatment of neurodegeneration in concert with, and inspired by, many others who have primed the study of the zebrafish to understand and search for a cure for disorders of the nervous system. Aware of the many advantages this vertebrate model holds, here we present an update on the recent zebrafish models available to study neurodegeneration with the goal of stimulating further interest and increasing the number of diseases and applications for which they can be exploited.We shall do so by citing and commenting on recent break-throughs made possible via zebrafish, highlighting their benefits for the testing of therapeutics and dissecting of disease mechanisms.

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Molecular Genetics of the Neuronal Ceroid Lipofuscinoses

Mole

2014

Encyclopedia of Life Sciences

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The neuronal ceroid lipofuscinoses (NCLs) are a group of clinically and genetically heterogenenous neurodegenerative disorders characterised by the accumulation of autofluorescent storage material in many cell types. Most display autosomal recessive inheritance. More than 400 mutations have been described in 13 genes: PPT1 , TPP1 , CLN3 , CLN5 , CLN6 , MFSD8 , CLN8 , CTSD, GRN, ATP13A2, KCTD7, CTSF and DNAJC5 , and none show obvious mutation hotspots. The functions of most of these genes remain elusive. The majority of the genetic defects identified are private, but there are geographically widespread or localised common founder mutations. The NCLs exemplify both phenotypic convergence and divergence, and there can be very wide disease severity caused by mutations in the same gene. Some recently identified mutations are in genes that are associated with other diseases. The recent expansion of knowledge in the genetic understanding of the NCLs is leading to improved diagnostic approaches, and the recent adoption of a new nomenclature. Key Concepts: More than 400 mutations are known across 13 genes causing disease in families diagnosed with NCL. Most NCLs are autosomal recessive. NCLs are a heterogenous group of disorders with common features of progressive degeneration of the brain, and often the retina, and intracellular storage of material similar to ceroid and lipofuscin. NCLs are monogenic disorders. One type of NCL is autosomal dominant. There remain families diagnosed with NCL in which the genetic cause is not yet determined.

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Use of model organisms for the study of neuronal ceroid lipofuscinosis

Cited by 84 publications

References 313 publications

Molecular neuropathology of the synapse in sheep with CLN5 Batten disease

Molecular neuropathology of the synapse in sheep with CLN5 Batten disease

New Zebrafish Models of Neurodegeneration

Molecular Genetics of the Neuronal Ceroid Lipofuscinoses

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