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David A Pearce - One of the best experts on this subject based on the ideXlab platform.
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therapeutic landscape for Batten Disease current treatments and future prospects
Nature Reviews Neurology, 2019Co-Authors: Tyler B Johnson, David A Pearce, Jacob T Cain, Katherine A White, Denia Ramirezmontealegre, Jill M WeimerAbstract:Batten Disease (also known as neuronal ceroid lipofuscinoses) constitutes a family of devastating lysosomal storage disorders that collectively represent the most common inherited paediatric neurodegenerative disorders worldwide. Batten Disease can result from mutations in 1 of 13 genes. These mutations lead to a group of Diseases with loosely overlapping symptoms and pathology. Phenotypically, patients with Batten Disease have visual impairment and blindness, cognitive and motor decline, seizures and premature death. Pathologically, Batten Disease is characterized by lysosomal accumulation of autofluorescent storage material, glial reactivity and neuronal loss. Substantial progress has been made towards the development of effective therapies and treatments for the multiple forms of Batten Disease. In 2017, cerliponase alfa (Brineura), a tripeptidyl peptidase enzyme replacement therapy, became the first globally approved treatment for CLN2 Batten Disease. Here, we provide an overview of the promising therapeutic avenues for Batten Disease, highlighting current FDA-approved clinical trials and prospective future treatments. In the past few years, substantial progress has been made towards effective treatment of Batten Disease, a family of paediatric neurodegenerative lysosomal storage disorders. In this Review, the authors discuss new therapies for Batten Disease, including cerliponase alfa, the first globally approved agent, and considers promising new therapeutic avenues for future treatments.
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characterization of a novel porcine model of cln3 Batten Disease
Molecular Genetics and Metabolism, 2019Co-Authors: Tyler B Johnson, David A Pearce, Katherine A White, Jonathan D Cooper, David A Sturdevant, Arlene V Drack, Sajag Bhattarai, Christopher S Rogers, Jill M WeimerAbstract:CLN3-Batten Disease is an autosomal-recessive disorder that results from mutations in CLN3. In the vast majority of cases, Disease onset occurs in early childhood, is characterized by progressive loss of vision, seizures and a failure in psychomotor development and is universally fatal by the third decade of life. Several mouse models of CLN3 have been developed that have provided insight into the pathological progression of this Disease including early glial activation followed by neuronal loss, however, many aspects of the Disease are not recapitulated in these mouse models. Porcine models hold the promise of a more accurate Disease model given the similarities that pigs and humans share in terms of development, anatomy, and physiology, and in particular, similarities in brain development such as perinatal growth spurt and brain structure. Furthermore, the shared characteristics of the human and porcine visual system make the pig a useful resource for studying macular-associated retinal Diseases that are not possible in mice. Additionally, the size of the pig would allow for the use advanced neuroimaging techniques such as MRI, CT and/or PET to model in vivo changes within the CNS longitudinally and track the success of potential therapeutics. Recently, we have developed a novel CLN3∆ex7-8/∆ex7-8 porcine model of CLN3-Batten Disease. Here we present initial characterization results showing behavioral, pathological, and visual deficits that mirror changes seen in human patients.
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Searching for novel biomarkers using a mouse model of CLN3-Batten Disease
2018Co-Authors: Derek Timm, David A Pearce, Jacob T Cain, Katherine A White, Ryan D. Geraets, Seung Yon Koh, Tammy Kielian, Michelle L. Hastings, Jill M WeimerAbstract:CLN3-Batten Disease is a rare, autosomal recessive disorder involving seizures, visual, motor and cognitive decline, and premature death. The Cln3Δex7/8 mouse model recapitulates several phenotypic characteristics of the most common 1.02kb Disease-associated deletion. Identification of reproducible biomarker(s) to facilitate longitudinal monitoring of Disease progression and provide readouts for therapeutic response has remained elusive. One factor that has complicated the identification of suitable biomarkers in this mouse model has been that variations in animal husbandry appear to significantly influence readouts. In the current study, we cross-compared a number of biological parameters in blood from Cln3Δex7/8 mice and control, non-Disease mice on the same genetic background from multiple animal facilities in an attempt to better define a surrogate marker of CLN3-Batten Disease. Interestingly, we found that significant differences between Batten and non-Disease mice found at one site were generally not maintained across different facilities. Our results suggest that colony variation in the Cln3Δex7/8 mouse model of CLN3-Batten Disease can influence potential biomarkers of the Disease.
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Batten Disease clinical aspects molecular mechanisms translational science and future directions
Journal of Child Neurology, 2013Co-Authors: Sarahbianca Dolisca, David A Pearce, Jonathan W. Mink, Mitali Mehta, Bernard L MariaAbstract:The neuronal ceroid lipofuscinoses, collectively the most common neurodegenerative disorders of childhood, are primarily caused by an autosomal recessive genetic mutation leading to a lysosomal storage Disease. Clinically, these Diseases manifest at varying ages of onset, and associated symptoms include cognitive decline, movement disorders, seizures, and retinopathy. The underlying cell biology and biochemistry that cause the clinical phenotypes of neuronal ceroid lipofuscinoses are still being elaborated. The 2012 Neurobiology of Disease in Children Symposium, held in conjunction with the 41st Annual Meeting of the Child Neurology Society, aimed to (1) provide a survey of the currently accepted forms of neuronal ceroid lipofuscinoses and their associated genetic mutations and clinical phenotypes; (2) highlight the specific pathology of Batten Disease; (3) discuss the contemporary understanding of the molecular mechanisms that lead to pathology; and (4) introduce strategies that are being translated from bench to bedside as potential therapeutics.
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age dependent therapeutic effect of memantine in a mouse model of juvenile Batten Disease
Neuropharmacology, 2012Co-Authors: Attila D Kovacs, Jonathan D Cooper, Andrew Wong, Angelika Saje, Serena Ramji, David A PearceAbstract:Currently there is no treatment for juvenile Batten Disease, a fatal childhood neurodegenerative disorder caused by mutations in the CLN3 gene. The Cln3-knockout (Cln3(Δex1-6)) mouse model recapitulates several features of the human disorder. Cln3(Δex1-6) mice, similarly to juvenile Batten Disease patients, have a motor coordination deficit detectable as early as postnatal day 14. Previous studies demonstrated that acute attenuation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-type glutamate receptor activity by the non-competitive AMPA antagonist, EGIS-8332, in both 1- and 6-7-month-old Cln3(Δex1-6) mice results in improvement in motor coordination. Here we show that acute inhibition of N-methyl-D-aspartate (NMDA)-type glutamate receptors by memantine (1 and 5 mg/kg i.p.) had no effect on the impaired motor coordination of one-month-old Cln3(Δex1-6) mice. At a later stage of the Disease, in 6-7-month-old Cln3(Δex1-6) mice, memantine induced a delayed but extended (8 days) improvement of motor skills similarly to that observed previously with EGIS-8332 treatment. An age-dependent therapeutic effect of memantine implies that the pathomechanism in juvenile Batten Disease changes during Disease progression. In contrast to acute treatment, repeated administration of memantine or EGIS-8332 (1 mg/kg, once a week for 4 weeks) to 6-month-old Cln3(Δex1-6) mice had no beneficial effect on motor coordination. Moreover, repeated treatments did not impact microglial activation or the survival of vulnerable neuron populations. Memantine did not affect astrocytosis in the cortex. EGIS-8332, however, decreased astrocytic activation in the somatosensory barrelfield cortex. Acute inhibition of NMDA receptors can induce a prolonged therapeutic effect, identifying NMDA receptors as a new therapeutic target for juvenile Batten Disease.
Jonathan D Cooper - One of the best experts on this subject based on the ideXlab platform.
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characterization of a novel porcine model of cln3 Batten Disease
Molecular Genetics and Metabolism, 2019Co-Authors: Tyler B Johnson, David A Pearce, Katherine A White, Jonathan D Cooper, David A Sturdevant, Arlene V Drack, Sajag Bhattarai, Christopher S Rogers, Jill M WeimerAbstract:CLN3-Batten Disease is an autosomal-recessive disorder that results from mutations in CLN3. In the vast majority of cases, Disease onset occurs in early childhood, is characterized by progressive loss of vision, seizures and a failure in psychomotor development and is universally fatal by the third decade of life. Several mouse models of CLN3 have been developed that have provided insight into the pathological progression of this Disease including early glial activation followed by neuronal loss, however, many aspects of the Disease are not recapitulated in these mouse models. Porcine models hold the promise of a more accurate Disease model given the similarities that pigs and humans share in terms of development, anatomy, and physiology, and in particular, similarities in brain development such as perinatal growth spurt and brain structure. Furthermore, the shared characteristics of the human and porcine visual system make the pig a useful resource for studying macular-associated retinal Diseases that are not possible in mice. Additionally, the size of the pig would allow for the use advanced neuroimaging techniques such as MRI, CT and/or PET to model in vivo changes within the CNS longitudinally and track the success of potential therapeutics. Recently, we have developed a novel CLN3∆ex7-8/∆ex7-8 porcine model of CLN3-Batten Disease. Here we present initial characterization results showing behavioral, pathological, and visual deficits that mirror changes seen in human patients.
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efficacy of phosphodiesterase 4 inhibitors in juvenile Batten Disease cln3
Annals of Neurology, 2016Co-Authors: Amy Aldrich, Jonathan D Cooper, Megan E Bosch, Rachel W Fallet, Jessica Odvody, Maria Burkovetskaya, Kakulavarapu Rama V Rao, Arlene V DrackAbstract:Objective: Juvenile Neuronal Ceroid Lipofuscinosis (JNCL), or juvenile Batten Disease, is a pediatric lysosomal storage Disease caused by autosomal recessive mutations in CLN3, typified by blindness, seizures, progressive cognitive and motor decline, and premature death. Currently, there is no treatment for JNCL that slows Disease progression, which highlights the need to explore novel strategies to extend the survival and quality-of-life of afflicted children. Cyclic AMP (cAMP) is a second messenger with pleiotropic effects, including regulating neuroinflammation and neuronal survival. Here we investigated whether three phosphodiesterase-4 (PDE4) inhibitors (rolipram, roflumilast, and PF-06266047) could mitigate behavioral deficits and cell-specific pathology in the Cln3Δex7/8 mouse model of JNCL. Methods: In a randomized, blinded study, wild type (WT) and Cln3Δex7/8 mice received PDE4 inhibitors daily beginning at 1 or 3 months of age and continuing for 6-9 months, with motor deficits assessed by accelerating rotarod testing. The effect of PDE4 inhibitors on cAMP levels, astrocyte and microglial activation (GFAP and CD68, respectively), lysosomal pathology (LAMP-1), and astrocyte glutamate transporter expression (GLAST) were also examined in WT and Cln3Δex7/8 animals. Results: cAMP levels were significantly reduced in the Cln3Δex7/8 brain, which were restored by PF-06266047. PDE4 inhibitors significantly improved motor function in Cln3Δex7/8 mice, attenuated glial activation and lysosomal pathology, and restored glutamate transporter expression to levels observed in WT animals with no evidence of toxicity as revealed by blood chemistry analysis. Interpretation: These studies reveal neuroprotective effects for PDE4 inhibitors in Cln3Δex7/8 mice and support their therapeutic potential in JNCL patients. This article is protected by copyright. All rights reserved.
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neurodegeneration and epilepsy in a zebrafish model of cln3 Disease Batten Disease
PLOS ONE, 2016Co-Authors: Kim Wager, Jonathan D Cooper, Anselm A Zdebik, Robert J Harvey, Claire RussellAbstract:The neuronal ceroid lipofuscinoses are a group of lysosomal storage disorders that comprise the most common, genetically heterogeneous, fatal neurodegenerative disorders of children. They are characterised by childhood onset, visual failure, epileptic seizures, psychomotor retardation and dementia. CLN3 Disease, also known as Batten Disease, is caused by autosomal recessive mutations in the CLN3 gene, 80-85% of which are a ~1 kb deletion. Currently no treatments exist, and after much suffering, the Disease inevitably results in premature death. The aim of this study was to generate a zebrafish model of CLN3 Disease using antisense morpholino injection, and characterise the pathological and functional consequences of Cln3 deficiency, thereby providing a tool for future drug discovery. The model was shown to faithfully recapitulate the pathological signs of CLN3 Disease, including reduced survival, neuronal loss, retinopathy, axonopathy, loss of motor function, lysosomal storage of subunit c of mitochondrial ATP synthase, and epileptic seizures, albeit with an earlier onset and faster progression than the human Disease. Our study provides proof of principle that the advantages of the zebrafish over other model systems can be utilised to further our understanding of the pathogenesis of CLN3 Disease and accelerate drug discovery.
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age dependent therapeutic effect of memantine in a mouse model of juvenile Batten Disease
Neuropharmacology, 2012Co-Authors: Attila D Kovacs, Jonathan D Cooper, Andrew Wong, Angelika Saje, Serena Ramji, David A PearceAbstract:Currently there is no treatment for juvenile Batten Disease, a fatal childhood neurodegenerative disorder caused by mutations in the CLN3 gene. The Cln3-knockout (Cln3(Δex1-6)) mouse model recapitulates several features of the human disorder. Cln3(Δex1-6) mice, similarly to juvenile Batten Disease patients, have a motor coordination deficit detectable as early as postnatal day 14. Previous studies demonstrated that acute attenuation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-type glutamate receptor activity by the non-competitive AMPA antagonist, EGIS-8332, in both 1- and 6-7-month-old Cln3(Δex1-6) mice results in improvement in motor coordination. Here we show that acute inhibition of N-methyl-D-aspartate (NMDA)-type glutamate receptors by memantine (1 and 5 mg/kg i.p.) had no effect on the impaired motor coordination of one-month-old Cln3(Δex1-6) mice. At a later stage of the Disease, in 6-7-month-old Cln3(Δex1-6) mice, memantine induced a delayed but extended (8 days) improvement of motor skills similarly to that observed previously with EGIS-8332 treatment. An age-dependent therapeutic effect of memantine implies that the pathomechanism in juvenile Batten Disease changes during Disease progression. In contrast to acute treatment, repeated administration of memantine or EGIS-8332 (1 mg/kg, once a week for 4 weeks) to 6-month-old Cln3(Δex1-6) mice had no beneficial effect on motor coordination. Moreover, repeated treatments did not impact microglial activation or the survival of vulnerable neuron populations. Memantine did not affect astrocytosis in the cortex. EGIS-8332, however, decreased astrocytic activation in the somatosensory barrelfield cortex. Acute inhibition of NMDA receptors can induce a prolonged therapeutic effect, identifying NMDA receptors as a new therapeutic target for juvenile Batten Disease.
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immunosuppression alters Disease severity in juvenile Batten Disease mice
Journal of Neuroimmunology, 2011Co-Authors: Sabrina S Seehafer, Denia Ramirezmontealegre, Jonathan D Cooper, Andrew Wong, Chunhung Chan, Julian A Castaneda, Michael Horak, Sarah M Ahmadi, Ming K Lim, David A PearceAbstract:article i nfo Autoantibodies to brain proteins are present in Juvenile Neuronal Ceroid Lipofuscinosis (Batten Disease) patients and in the Cln3 �/� mouse model of this Disease, suggesting an autoimmune component to pathogenesis. Using genetic or pharmaceutical approaches to attenuate this immune response in Cln3 �/� mice, we demonstrate decreased neuroinflammation, decreased deposition of immunoglobulin G in the brain and protection of vulnerable neuron populations. Moreover, immune suppression results in a significant improvement in motor performance providing for the first plausible therapeutic approach for juvenile Batten Disease.
Anu Jalanko - One of the best experts on this subject based on the ideXlab platform.
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novel interactions of cln3 protein link Batten Disease to dysregulation of fodrin na k atpase complex
Experimental Cell Research, 2008Co-Authors: Kristiina Uusirauva, Kaisu Luiro, Outi Kopra, Aija Kyttala, Kimmo Tanhuanpaa, Pablo Martinvasallo, Anu JalankoAbstract:Juvenile neuronal ceroid lipofuscinosis (JNCL, Batten Disease) is the most common progressive neurodegenerative disorder of childhood. CLN3, the transmembrane protein underlying JNCL, is proposed to participate in multiple cellular events including membrane trafficking and cytoskeletal functions. We demonstrate here that CLN3 interacts with the plasma membrane-associated cytoskeletal and endocytic fodrin and the associated Na(+), K(+) ATPase. The ion pumping activity of Na(+), K(+) ATPase was unchanged in Cln3(-/-) mouse primary neurons. However, the immunostaining pattern of fodrin appeared abnormal in JNCL fibroblasts and Cln3(-/-) mouse brains suggesting disturbances in the fodrin cytoskeleton. Furthermore, the basal subcellular distribution as well as ouabain-induced endocytosis of neuron-specific Na(+), K(+) ATPase were remarkably affected in Cln3(-/-) mouse primary neurons. These data suggest that CLN3 is involved in the regulation of plasma membrane fodrin cytoskeleton and consequently, the plasma membrane association of Na(+), K(+) ATPase. Most of the processes regulated by multifunctional fodrin and Na(+), K(+) ATPase are also affected in JNCL and Cln3-deficiency implicating that dysregulation of fodrin cytoskeleton and non-pumping functions of Na(+), K(+) ATPase may play a role in the neuronal degeneration in JNCL.
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Batten Disease jncl is linked to disturbances in mitochondrial cytoskeletal and synaptic compartments
Journal of Neuroscience Research, 2006Co-Authors: Kaisu Luiro, Hannah M Mitchison, Outi Kopra, Tomas Blom, Massimiliano Gentile, Iiris Hovatta, Kid Tornquist, Anu JalankoAbstract:Intracellular pathways leading to neuronal degeneration are poorly understood in the juvenile neuronal ceroid lipofuscinosis (JNCL, Batten Disease), caused by mutations in the CLN3 gene. To elucidate the early pathology, we carried out comparative global transcript profiling of the embryonic, primary cultures of the Cln3-/- mouse neurons. Statistical and functional analyses delineated three major cellular pathways or compartments affected: mitochondrial glucose metabolism, cytoskeleton, and synaptosome. Further functional studies showed a slight mitochondrial dysfunction and abnormalities in the microtubule cytoskeleton plus-end components. Synaptic dysfunction was also indicated by the pathway analysis, and by the gross upregulation of the G protein beta 1 subunit, known to regulate synaptic transmission via the voltage-gated calcium channels. Intracellular calcium imaging showed a delay in the recovery from depolarization in the Cln3-/- neurons, when the N-type Ca2+ channels had been blocked. The data suggests a link between the mitochondrial dysfunction and cytoskeleton-mediated presynaptic inhibition, thus providing a foundation for further investigation of the Disease mechanism underlying JNCL Disease.
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ap 1 and ap 3 facilitate lysosomal targeting of Batten Disease protein cln3 via its dileucine motif
Journal of Biological Chemistry, 2005Co-Authors: Aija Kyttala, Anu Jalanko, Kristiina Yliannala, Peter Schu, Paul J LuzioAbstract:CLN3 is a transmembrane protein with a predominant localization in lysosomes in non-neuronal cells but is also found in endosomes and the synaptic region in neuronal cells. Mutations in the CLN3 gene result in juvenile neuronal ceroid lipofuscinosis or Batten Disease, which currently is the most common cause of childhood dementia. We have recently reported that the lysosomal targeting of CLN3 is facilitated by two targeting motifs: a dileucine-type motif in a cytoplasmic loop domain and an unusual motif in the carboxyl-terminal cytoplasmic tail comprising a methionine and a glycine separated by nine amino acids (Kyttala, A., Ihrke, G., Vesa, J., Schell, M. J., and Luzio, J. P. (2004) Mol. Biol. Cell 15, 1313-1323). In the present study, we investigated the pathways and mechanisms of CLN3 sorting using biochemical binding assays and immunofluorescence methods. The dileucine motif of CLN3 bound both AP-1 and AP-3 in vitro, and expression of mutated CLN3 in AP-1- or AP-3-deficient mouse fibroblasts showed that both adaptor complexes are required for sequential sorting of CLN3 via this motif. Our data indicate the involvement of complex sorting machinery in the trafficking of CLN3 and emphasize the diversity of parallel and sequential sorting pathways in the trafficking of membrane proteins.
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interconnections of cln3 hook1 and rab proteins link Batten Disease to defects in the endocytic pathway
Human Molecular Genetics, 2004Co-Authors: Kaisu Luiro, Irma Jarvela, Aija Kyttala, Kristiina Yliannala, Laura Ahtiainen, Heidi Maunu, Anu JalankoAbstract:The endosomal/lysosomal transmembrane protein CLN3 is mutated in the Batten Disease (juvenile neuronal ceroid lipofuscinosis, JNCL). However, the molecular mechanism of JNCL pathogenesis and the exact function of the CLN3 protein have remained unclear. Previous studies have shown that deletion of BTN1, the yeast orthologue of CLN3, leads to increased expression of BTN2. BTN2 encodes Btn2p, a proposed homologue to a novel microtubule-binding protein Hook1, which regulates endocytosis in Drosophila. We analysed here the putative interconnection between CLN3 and Hook1 in the mammalian cells and discovered that overexpression of human CLN3 induces aggregation of Hook1 protein, potentially by mediating its dissociation from the microtubules. Using in vitro binding assay we were able to demonstrate a weak interaction between Hook1 and the cytoplasmic segments of CLN3. We also found receptor-mediated endocytosis to be defective in CLN3-deficient JNCL fibroblasts, connecting CLN3, Hook1 and endocytosis in the mammalian system. Moreover, co-immunoprecipitation experiments showed that Hook1 physically interacts with endocytic Rab7, Rab9 and Rab11, hence delineating a manifold role for mammalian Hook1 in membrane trafficking events. These novel interactions between the microtubule-binding Hook1 and the large family of Rab GTPases also suggest a link between CLN3 function, microtubule cytoskeleton and endocytic membrane trafficking.
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cln3 protein is targeted to neuronal synapses but excluded from synaptic vesicles new clues to Batten Disease
Human Molecular Genetics, 2001Co-Authors: Kaisu Luiro, Outi Kopra, Maarit Lehtovirta, Anu JalankoAbstract:Batten Disease (juvenile neuronal ceroid lipofuscinosis, JNCL), the most common neurodegenerative Disease of childhood, is caused by mutations in the CLN3 gene encoding a putative transmembrane protein. The function of CLN3 is currently unknown but it has been shown to localize in the endosomal/lysosomal compartments of non-neuronal cells. In addition, several other intracellular localizations have been proposed and the controversy of the reports suggests that CLN3 may have different intracellular localization in different cell types. Batten Disease severely affects neuronal cells but leaves other organs clinically unaffected, and thus it is of utmost importance to approach the Disease mechanism by studying the expression and localization of CLN3 in the brain and neuronal cells. We have analysed here CLN3 in the mouse brain using in situ hybridization, immunohistochemical staining and western blot analysis of subcellular fractions. As visual deterioration is the hallmark of Batten Disease we have set up primary retinal cultures from the mouse and analysed both endogenous mouse CLN3 and Semliki Forest virus-mediated human CLN3 localization using immunofluorescence staining and confocal microscopy. We demonstrate that CLN3 is abundantly expressed in neuronal cells, especially in the cortex, hippocampus and cerebellum of the adult mouse brain. Furthermore, our results indicate that in neurons CLN3 is not solely a lysosomal protein. It is localized in the synaptosomes but, interestingly, is not targeted to the synaptic vesicles. The novel localization of CLN3 directs attention towards molecular alterations at the synapses. This should yield important clues about the mechanisms of neurodegeneration in Batten Disease.
David N Palmer - One of the best experts on this subject based on the ideXlab platform.
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intravitreal gene therapy protects against retinal dysfunction and degeneration in sheep with cln5 Batten Disease
Experimental Eye Research, 2021Co-Authors: Samantha J Murray, Nadia L Mitchell, David N Palmer, Katharina Russell, Tracy R Melzer, Steven J Gray, Stephen J HeapAbstract:Neuronal ceroid lipofuscinoses (NCL; Batten Disease) are a group of inherited neurodegenerative Diseases primarily affecting children. A common feature across most NCLs is the progressive loss of vision. We performed intravitreal injections of self-complementary AAV9 vectors packaged with either ovine CLN5 or CLN6 into one eye of 3-month-old CLN5-/- or CLN6-/- animals, respectively. Electroretinography (ERG) was performed every month following treatment, and retinal histology was assessed post-mortem in the treated compared to untreated eye. In CLN5-/- animals, ERG amplitudes were normalised in the treated eye whilst the untreated eye declined in a similar manner to CLN5 affected controls. In CLN6-/- animals, ERG amplitudes in both eyes declined over time although the treated eye showed a slower decline. Post-mortem examination revealed significant attenuation of retinal atrophy and lysosomal storage body accumulation in the treated eye compared with the untreated eye in CLN5-/- animals. This proof-of-concept study provides the first observation of efficacious intravitreal gene therapy in a large animal model of NCL. In particular, the single administration of AAV9-mediated intravitreal gene therapy can successfully ameliorate retinal deficits in CLN5-/- sheep. Combining ocular gene therapy with brain-directed therapy presents a promising treatment strategy to be used in future sheep trials aiming to halt neurological and retinal Disease in CLN5 Batten Disease.
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RESEARCH ARTICLE Rapid and Progressive Regional Brain Atrophy in CLN6 Batten Disease Affected Sheep Measured with Longitudinal Magnetic Resonance Imaging
2016Co-Authors: Stephen J Sawiak, Sunthara Rajan Perumal, Skye R Rudiger, Loren Matthews, Clive J Mclaughlan, Simon C Bawden, David N Palmer, L. Mitchell, Timothy Kuchel, Jennifer A MortonAbstract:Variant late-infantile Batten Disease is a neuronal ceroid lipofuscinosis caused by mutations in CLN6. It is a recessive genetic lysosomal storage Disease characterised by progressive neurodegeneration. It starts insidiously and leads to blindness, epilepsy and dementia in affected children. Sheep that are homozygous for a natural mutation in CLN6 have an ovine form of Batten Disease Here, we used in vivomagnetic resonance imaging to track brain changes in 4 unaffected carriers and 6 affected Batten Disease sheep. We scanned each sheep 4 times, between 17 and 22 months of age. Cortical atrophy in all sheep was pro-nounced at the baseline scan in all affected Batten Disease sheep. Significant atrophy was also present in other brain regions (caudate, putamen and amygdala). Atrophy continued measurably in all of these regions during the study. Longitudinal MRI in sheep was sensitive enough to measure significant volume changes over the relatively short study period, even in the cortex, where nearly 40 % of volume was already lost at the start of the study. Thus longitudinal MRI could be used to study the dynamics of progression of neurodegenerative changes in sheep models of Batten Disease, as well as to assess therapeutic efficacy
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molecular neuropathology of the synapse in sheep with cln5 Batten Disease
Brain and behavior, 2015Co-Authors: Ines S Amorim, Stephen J Sawiak, Nadia L Mitchell, David N Palmer, Roger Mason, Thomas M Wishart, Thomas H GillingwaterAbstract:Aims 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.
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rapid and progressive regional brain atrophy in cln6 Batten Disease affected sheep measured with longitudinal magnetic resonance imaging
PLOS ONE, 2015Co-Authors: Stephen J Sawiak, Sunthara Rajan Perumal, Skye R Rudiger, Loren Matthews, Nadia L Mitchell, Clive J Mclaughlan, Simon C Bawden, David N Palmer, Timothy R Kuchel, Jennifer A MortonAbstract:Variant late-infantile Batten Disease is a neuronal ceroid lipofuscinosis caused by mutations in CLN6. It is a recessive genetic lysosomal storage Disease characterised by progressive neurodegeneration. It starts insidiously and leads to blindness, epilepsy and dementia in affected children. Sheep that are homozygous for a natural mutation in CLN6 have an ovine form of Batten Disease Here, we used in vivo magnetic resonance imaging to track brain changes in 4 unaffected carriers and 6 affected Batten Disease sheep. We scanned each sheep 4 times, between 17 and 22 months of age. Cortical atrophy in all sheep was pronounced at the baseline scan in all affected Batten Disease sheep. Significant atrophy was also present in other brain regions (caudate, putamen and amygdala). Atrophy continued measurably in all of these regions during the study. Longitudinal MRI in sheep was sensitive enough to measure significant volume changes over the relatively short study period, even in the cortex, where nearly 40% of volume was already lost at the start of the study. Thus longitudinal MRI could be used to study the dynamics of progression of neurodegenerative changes in sheep models of Batten Disease, as well as to assess therapeutic efficacy.
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translational neurophysiology in sheep measuring sleep and neurological dysfunction in cln5 Batten Disease affected sheep
Brain, 2015Co-Authors: Nikolas Perentos, Nadia L Mitchell, David N Palmer, Amadeu Quelhas Martins, Thomas C Watson, Ullrich Bartsch, Matthew W Jones, Anne Jennifer MortonAbstract:Creating valid mouse models of slowly progressing human neurological Diseases is challenging, not least because the short lifespan of rodents confounds realistic modelling of Disease time course. With their large brains and long lives, sheep offer significant advantages for translational studies of human Disease. Here we used normal and CLN5 Batten Disease affected sheep to demonstrate the use of the species for studying neurological function in a model of human Disease. We show that electroencephalography can be used in sheep, and that longitudinal recordings spanning many months are possible. This is the first time such an electroencephalography study has been performed in sheep. We characterized sleep in sheep, quantifying characteristic vigilance states and neurophysiological hallmarks such as sleep spindles. Mild sleep abnormalities and abnormal epileptiform waveforms were found in the electroencephalographies of Batten Disease affected sheep. These abnormalities resemble the epileptiform activity seen in children with Batten Disease and demonstrate the translational relevance of both the technique and the model. Given that both spontaneous and engineered sheep models of human neurodegenerative Diseases already exist, sheep constitute a powerful species in which longitudinal in vivo studies can be conducted. This will advance our understanding of normal brain function and improve our capacity for translational research into neurological disorders.
Hannah M Mitchison - One of the best experts on this subject based on the ideXlab platform.
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altered cerebellar short term plasticity but no change in postsynaptic ampa type glutamate receptors in a mouse model of juvenile Batten Disease
eNeuro 5 (2) Article e0387. (2018), 2018Co-Authors: Dorota Studniarczyk, Hannah M Mitchison, Elizabeth L Needham, Mark Farrant, S G CullcandyAbstract:Abstract Juvenile Batten Disease is the most common progressive neurodegenerative disorder of childhood. It is associated with mutations in the CLN3 gene, causing loss of function of CLN3 protein and degeneration of cerebellar and retinal neurons. It has been proposed that changes in granule cell AMPA-type glutamate receptors (AMPARs) contribute to the cerebellar dysfunction. In this study we compared AMPAR properties and synaptic transmission in cerebellar granule cells from wild-type and Cln3 knockout mice. In Cln3 Δ ex1–6 cells the amplitude of AMPA-evoked whole-cell currents was unchanged. Similarly, we found no change in the amplitude, kinetics, or rectification of synaptic currents evoked by individual quanta, or in their underlying single-channel conductance. We found no change in cerebellar expression of GluA2 or GluA4 protein. By contrast, we observed a reduced number of quantal events following mossy-fiber stimulation in Sr 2+ , altered short-term plasticity in conditions of reduced extracellular Ca 2+ , and reduced mossy fiber vesicle number. Thus, while our results suggest early presynaptic changes in the Cln3 Δ ex1–6 mouse model of juvenile Batten Disease, they reveal no evidence for altered postsynaptic AMPARs. Significance Statement Juvenile Batten Disease is an inherited lysosomal storage disorder that affects children and leads to premature death. Caused by mutations in the CLN3 gene, it results in a loss of CLN3 protein and neuronal degeneration. It has been proposed that changes in granule cell AMPA-type glutamate receptors contribute to cerebellar dysfunction. Here, we show that the properties of postsynaptic AMPA receptors in granule cells from juvenile Cln3 Δ ex1–6 mice are unaltered. Instead, loss of CLN3 protein leads to early presynaptic changes and altered short-term plasticity.
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Batten Disease jncl is linked to disturbances in mitochondrial cytoskeletal and synaptic compartments
Journal of Neuroscience Research, 2006Co-Authors: Kaisu Luiro, Hannah M Mitchison, Outi Kopra, Tomas Blom, Massimiliano Gentile, Iiris Hovatta, Kid Tornquist, Anu JalankoAbstract:Intracellular pathways leading to neuronal degeneration are poorly understood in the juvenile neuronal ceroid lipofuscinosis (JNCL, Batten Disease), caused by mutations in the CLN3 gene. To elucidate the early pathology, we carried out comparative global transcript profiling of the embryonic, primary cultures of the Cln3-/- mouse neurons. Statistical and functional analyses delineated three major cellular pathways or compartments affected: mitochondrial glucose metabolism, cytoskeleton, and synaptosome. Further functional studies showed a slight mitochondrial dysfunction and abnormalities in the microtubule cytoskeleton plus-end components. Synaptic dysfunction was also indicated by the pathway analysis, and by the gross upregulation of the G protein beta 1 subunit, known to regulate synaptic transmission via the voltage-gated calcium channels. Intracellular calcium imaging showed a delay in the recovery from depolarization in the Cln3-/- neurons, when the N-type Ca2+ channels had been blocked. The data suggests a link between the mitochondrial dysfunction and cytoskeleton-mediated presynaptic inhibition, thus providing a foundation for further investigation of the Disease mechanism underlying JNCL Disease.
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functional categorization of gene expression changes in the cerebellum of a cln3 knockout mouse model for Batten Disease
Molecular Genetics and Metabolism, 2003Co-Authors: Andrew I Brooks, Subrata Chattopadhyay, Hannah M Mitchison, Robert L Nussbaum, David A PearceAbstract:Juvenile neuronal ceroid lipofuscinosis (JNCL or Batten Disease) is the most common progressive neurodegenerative disorder of childhood. The Disease is inherited in an autosomal recessive manner and is the result of mutations in the CLN3 gene. One brain region severely affected in Batten Disease is the cerebellum. Using a mouse model for Batten Disease which shares pathological similarities to the Disease in humans we have used oligonucleotide arrays to profile approximately 19,000 mRNAs in the cerebellum. We have identified reproducible changes of twofold or more in the expression of 756 gene products in the cerebellum of 10-week-old Cln3-knockout mice as compared to wild-type controls. We have subsequently divided these genes with altered expression into 14 functional categories. We report a significant alteration in expression of genes associated with neurotransmission, neuronal cell structure and development, immune response and inflammation, and lipid metabolism. An apparent shift in metabolism toward gluconeogenesis is also evident in Cln3-knockout mice. Further experimentation will be necessary to understand the contribution of these changes in expression to a Disease state. Detailed analysis of the functional consequences of altered expression of genes in the cerebellum of the Cln3-knockout mice may provide valuable clues in understanding the molecular basis of the pathological mechanisms underlying Batten Disease.
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targeted disruption of the cln3 gene provides a mouse model for Batten Disease
Neurobiology of Disease, 1999Co-Authors: Hannah M Mitchison, David J Bernard, Nicholas D E Greene, Jonathan D Cooper, Mohammed A Junaid, Raju K Pullarkat, Nanneke De Vos, Martijn H Breuning, Jennie W Owens, William C MobleyAbstract:Batten Disease, a degenerative neurological disorder with juvenile onset, is the most common form of the neuronal ceroid lipofuscinoses. Mutations in the CLN3 gene cause Batten Disease. To facilitate studies of Batten Disease pathogenesis and treatment, a murine model was created by targeted disruption of the Cln3 gene. Mice homozygous for the disrupted Cln3 allele had a neuronal storage disorder resembling that seen in Batten Disease patients: there was widespread and progressive intracellular accumulation of autofluorescent material that by EM displayed a multilamellar rectilinear/fingerprint appearance. Inclusions contained subunit c of mitochondrial ATP synthase. Mutant animals also showed neuropathological abnormalities with loss of certain cortical interneurons and hypertrophy of many interneuron populations in the hippocampus. Finally, as is true in Batten Disease patients, there was increased activity in the brain of the lysosomal protease Cln2/TPP-1. Our findings are evidence that the Cln3-deficient mouse provides a valuable model for studying Batten Disease.
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spectrum of mutations in the Batten Disease gene cln3
American Journal of Human Genetics, 1997Co-Authors: Patricia B Munroe, Rose-mary Boustany, Hannah M Mitchison, Nanneke De Vos, Martijn H Breuning, Terry J Lerner, John W Anderson, A M Orawe, Peter E M Taschner, Mark R GardinerAbstract:Batten Disease (juvenile-onset neuronal ceroid lipofuscinosis [JNCL]) is an autosomal recessive condition characterized by accumulation of lipopigments (lipofuscin and ceroid) in neurons and other cell types. The Batten Disease gene, CLN3, was recently isolated, and four Disease-causing mutations were identified, including a 1.02-kb deletion that is present in the majority of patients (The International Batten Disease Consortium 1995). One hundred eighty-eight unrelated patients with JNCL were screened in this study to determine how many Disease chromosomes carried the 1.02-kb deletion and how many carried other mutations in CLN3. One hundred thirty-nine patients (74%) were found to have the 1.02-kb deletion on both chromosomes, whereas 49 patients (41 heterozygous for the 1.02-kb deletion) had mutations other than the 1.02-kb deletion. SSCP analysis and direct sequencing were used to screen for new mutations in these individuals. Nineteen novel mutations were found: six missense mutations, five nonsense mutations, three small deletions, three small insertions, one intronic mutation, and one splice-site mutation. This report brings the total number of Disease-associated mutations in CLN3 to 23. All patients homozygous for mutations predicted to give rise to truncated proteins were found to have classical JNCL. However, a proportion of the patients (n = 4) who were compound heterozygotes for a missense mutation and the 1.02-kb deletion were found to display an atypical phenotype that was dominated by visual failure rather than by severe neurodegeneration. All missense mutations were found to affect residues conserved between the human protein and homologues in diverse species.
