The Experts below are selected from a list of 234 Experts worldwide ranked by ideXlab platform
Rosanne M. Taylor - One of the best experts on this subject based on the ideXlab platform.
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Associations between neurologic dysfunction and lesions in canine Fucosidosis.
Genes brain and behavior, 2016Co-Authors: Jessica L Fletcher, Rosanne M. TaylorAbstract:Canine Fucosidosis in English Springer spaniels is the only animal model of the neurovisceral lysosomal storage disease Fucosidosis available for preclinical therapeutic trials. For this reason, it is crucial to identify critical time points in disease progression, and if there are particular lesions associated with specific aspects of neurologic dysfunction. Historical records of 53 canine Fucosidosis cases from 1979 to 2009 containing a neurologic dysfunction score assessing motor, behavioral and sensory dysfunction were interrogated by statistical analysis. Motor and behavioral dysfunction scores assessing gait deficits and apprehensive behavior first significantly increased at 12-17 months, and increased at each 6-month interval thereafter. Sensory dysfunction scores, assessing hearing loss, balance and vision deterioration, did not significantly increase until 18-23 months, and coincided with a rapid decline in neurologic function. Regression analysis incorporating published neuropathology data, measured by image analysis, identified neuroinflammation and apoptotic cell death as significant informative predictors of increasing neurologic dysfunction. These findings indicate that the level of neuropathology required to induce consistent and conspicuous clinical signs in canine Fucosidosis is reached by approximately 12 months of age in the absence of other disease processes. Significant association between neuroinflammation and apoptotic cell death also suggests that specifically targeting these lesions combined with enzyme replacement in future studies may reduce disease burden in Fucosidosis. Overall, examining this historical clinical data to identify associations between the extent of neuropathology and degree of clinical dysfunction provides a useful reference tool for monitoring disease and evaluating therapeutic trials conducted in canine Fucosidosis.
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Therapy Development for the Lysosomal Storage Disease Fucosidosis using the Canine Animal Model.
Pediatric endocrinology reviews : PER, 2016Co-Authors: Jessica L Fletcher, Rosanne M. TaylorAbstract:Abstract Fucosidosis (OMIM 23000) is an inherited neurodegenerative lysosomal storage disease caused by a deficiency of the lysosomal hydrolase a-L-fucosidase due to mutations in the FUCA1 gene. Without enzyme-targeted therapy patients rarely survive beyond the first decade of life, and therapy options other than supportive care are limited. Hematopoietic transplants, first developed in the Fucosidosis dog model, are the only treatment option available capable of delaying the disease course. However, due to the risks and exclusion criteria of this treatment additional therapies are required. The development of additional therapies including intravenous and intra-cerebrospinal fluid enzyme replacement therapy and gene therapy, which have been trialed in the canine model, will be discussed.
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The effects of intracisternal enzyme replacement versus sham treatment on central neuropathology in preclinical canine Fucosidosis
Orphanet journal of rare diseases, 2015Co-Authors: Gauthami S. Kondagari, Jessica L Fletcher, Peter Williamson, John J. Hopwood, Rachel E. Cruz, Rosanne M. TaylorAbstract:Fucosidosis results from lack of α-L-fucosidase activity, with accumulation of fucose-linked substrates in the nervous system and viscera leading to progressive motor and mental deterioration, and death. The naturally occurring dog model of Fucosidosis was used to evaluate the neuropathological responses to partial enzyme replacement, and substrate reduction in early disease following treatment with recombinant canine α-L-fucosidase delivered through cerebrospinal fluid. Neuropathology in both treated (n = 3) and untreated Fucosidosis-affected (n = 3) animals was evaluated with immunohistochemistry, image analysis, manual quantification and gene expression analysis and compared with unaffected age-matched controls (n = 3) in an extension of our previous biochemical report on the same cohort. Data were analyzed by ANOVA. Quantification demonstrated a consistent trend to reduction in vacuolation, pyramidal neuron loss, astrocytosis, microgliosis, perivascular storage, apoptosis, oligodendrocyte loss, and hypomyelination throughout the central nervous system of enzyme treated animals compared to placebo-treated, age-matched affected controls. Key lesions including lysosomal expansion in neurons of deep cortex, astrocytosis in cerebral cortex and medulla, and increased lysosomal membrane associated protein-1 (LAMP-1) gene expression were ameliorated in treated animals. There was no change in spheroid formation and loss of Purkinje cells, but Purkinje cell vulnerability to apoptosis was reduced with treatment. Despite reduced severity of Fucosidosis neuropathology with partial enzyme replacement, more complete and sustained biochemical correction is required to halt neuropathological processes in this large animal model of lysosomal storage disease.
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oligodendrocyte loss during the disease course in a canine model of the lysosomal storage disease Fucosidosis
Journal of Neuropathology and Experimental Neurology, 2014Co-Authors: Jessica L Fletcher, Gauthami S. Kondagari, Charles H Vite, Peter Williamson, Rosanne M. TaylorAbstract:Hypomyelination is a poorly understood feature of many neurodegenerative lysosomal storage diseases, including Fucosidosis in children and animals. To gain insight into hypomyelination in Fucosidosis, we investigated lysosomal storage, oligodendrocyte death, and axonal and neuron loss in CNS tissues of Fucosidosis-affected dogs aged 3 weeks to 42 months using immunohistochemistry, electron microscopy, and gene expression assays. Vacuole accumulation in Fucosidosis oligodendrocytes commenced by 5 weeks of age; all oligodendrocytes were affected by 16 weeks. Despite progressive vacuolation, mature oligodendrocyte loss by apoptosis (caspase-6 positive) in the corpus callosum and cerebellar white matter stabilized by 16 weeks, with no further subsequent loss. Axonal neurofilament loss progressed only in late disease, suggesting that disturbed axon-oligodendrocyte interactions are unlikely to be the primary cause of hypomyelination. A 67% decline in the number of Purkinje cell layer oligodendrocytes coincided with a 67% increase in the number of caspase-6-positive Purkinje cells at 16 weeks, suggesting that early oligodendrocyte loss contributes to Purkinje cell apoptosis. Fucosidosis hypomyelination appeared to follow normal spatiotemporal patterns of myelination, with greater loss of oligodendrocytes and larger downregulation of CNP, MAL, and PLP1 genes at 16 weeks in the cerebellum versus the frontal cortex. These studies suggest that survival of oligodendrocytes in Fucosidosis is limited during active myelination, although the mechanisms remain unknown.
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Myelin genes are downregulated in canine Fucosidosis.
Biochimica et biophysica acta, 2011Co-Authors: Jessica L Fletcher, Gauthami S. Kondagari, Peter Williamson, Amanda L. Wright, Peter C. Thomson, Rosanne M. TaylorAbstract:The processes regulating the complex neurodegenerative cascade of vacuolation, neuroinflammation, neuronal loss and myelin deficits in Fucosidosis, a neurological lysosomal storage disorder, remain unclear. To elucidate these processes the gene expression profile of the cerebral cortex from untreated and intrathecal enzyme replacement therapy treated Fucosidosis pups and age-matched unaffected controls were examined. Neuroinflammation and cell death processes were identified to have a major role in Fucosidosis pathophysiology with 37% of differentially expressed (DE) genes involved in these processes. Critical, specific, early decreases in expression levels of key genes in myelin assembly were identified by gene expression profiling, including myelin-associated glycoprotein (MAG), myelin and lymphocyte protein (MAL), and oligodendrocyte myelin paranodal and inner loop protein (OPALIN). These gene expression changes may be indicative of early neuronal loss causing reduced electrical impulses required for oligodendrocyte maturation.
Stephen Wood - One of the best experts on this subject based on the ideXlab platform.
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Cultured Fucosidosis fibroblasts: A simple technique demonstrating storage of tritiated‐fucose labeled material
Clinical genetics, 2008Co-Authors: Stephen WoodAbstract:Incorporation of tritiated fucose into the acid-soluble and acid-insoluble fractions of cultured Fucosidosis and control fibroblast monolayers was determined over a 10-day period. Fucosidosis cells incorporated significantly more label into the acid-soluble, but not the acid-insoluble fraction, than control cells. The ratio of acid-soluble to acid-insoluble radioactivity increased linearly from 1 to 10 days for the Fucosidosis cells, indicating the storage of low molecular weight partial degradation products.
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cultured Fucosidosis fibroblasts a simple technique demonstrating storage of tritiated fucose labeled material
Clinical Genetics, 2008Co-Authors: Stephen WoodAbstract:Incorporation of tritiated fucose into the acid-soluble and acid-insoluble fractions of cultured Fucosidosis and control fibroblast monolayers was determined over a 10-day period. Fucosidosis cells incorporated significantly more label into the acid-soluble, but not the acid-insoluble fraction, than control cells. The ratio of acid-soluble to acid-insoluble radioactivity increased linearly from 1 to 10 days for the Fucosidosis cells, indicating the storage of low molecular weight partial degradation products.
Jessica L Fletcher - One of the best experts on this subject based on the ideXlab platform.
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Associations between neurologic dysfunction and lesions in canine Fucosidosis.
Genes brain and behavior, 2016Co-Authors: Jessica L Fletcher, Rosanne M. TaylorAbstract:Canine Fucosidosis in English Springer spaniels is the only animal model of the neurovisceral lysosomal storage disease Fucosidosis available for preclinical therapeutic trials. For this reason, it is crucial to identify critical time points in disease progression, and if there are particular lesions associated with specific aspects of neurologic dysfunction. Historical records of 53 canine Fucosidosis cases from 1979 to 2009 containing a neurologic dysfunction score assessing motor, behavioral and sensory dysfunction were interrogated by statistical analysis. Motor and behavioral dysfunction scores assessing gait deficits and apprehensive behavior first significantly increased at 12-17 months, and increased at each 6-month interval thereafter. Sensory dysfunction scores, assessing hearing loss, balance and vision deterioration, did not significantly increase until 18-23 months, and coincided with a rapid decline in neurologic function. Regression analysis incorporating published neuropathology data, measured by image analysis, identified neuroinflammation and apoptotic cell death as significant informative predictors of increasing neurologic dysfunction. These findings indicate that the level of neuropathology required to induce consistent and conspicuous clinical signs in canine Fucosidosis is reached by approximately 12 months of age in the absence of other disease processes. Significant association between neuroinflammation and apoptotic cell death also suggests that specifically targeting these lesions combined with enzyme replacement in future studies may reduce disease burden in Fucosidosis. Overall, examining this historical clinical data to identify associations between the extent of neuropathology and degree of clinical dysfunction provides a useful reference tool for monitoring disease and evaluating therapeutic trials conducted in canine Fucosidosis.
-
Therapy Development for the Lysosomal Storage Disease Fucosidosis using the Canine Animal Model.
Pediatric endocrinology reviews : PER, 2016Co-Authors: Jessica L Fletcher, Rosanne M. TaylorAbstract:Abstract Fucosidosis (OMIM 23000) is an inherited neurodegenerative lysosomal storage disease caused by a deficiency of the lysosomal hydrolase a-L-fucosidase due to mutations in the FUCA1 gene. Without enzyme-targeted therapy patients rarely survive beyond the first decade of life, and therapy options other than supportive care are limited. Hematopoietic transplants, first developed in the Fucosidosis dog model, are the only treatment option available capable of delaying the disease course. However, due to the risks and exclusion criteria of this treatment additional therapies are required. The development of additional therapies including intravenous and intra-cerebrospinal fluid enzyme replacement therapy and gene therapy, which have been trialed in the canine model, will be discussed.
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The effects of intracisternal enzyme replacement versus sham treatment on central neuropathology in preclinical canine Fucosidosis
Orphanet journal of rare diseases, 2015Co-Authors: Gauthami S. Kondagari, Jessica L Fletcher, Peter Williamson, John J. Hopwood, Rachel E. Cruz, Rosanne M. TaylorAbstract:Fucosidosis results from lack of α-L-fucosidase activity, with accumulation of fucose-linked substrates in the nervous system and viscera leading to progressive motor and mental deterioration, and death. The naturally occurring dog model of Fucosidosis was used to evaluate the neuropathological responses to partial enzyme replacement, and substrate reduction in early disease following treatment with recombinant canine α-L-fucosidase delivered through cerebrospinal fluid. Neuropathology in both treated (n = 3) and untreated Fucosidosis-affected (n = 3) animals was evaluated with immunohistochemistry, image analysis, manual quantification and gene expression analysis and compared with unaffected age-matched controls (n = 3) in an extension of our previous biochemical report on the same cohort. Data were analyzed by ANOVA. Quantification demonstrated a consistent trend to reduction in vacuolation, pyramidal neuron loss, astrocytosis, microgliosis, perivascular storage, apoptosis, oligodendrocyte loss, and hypomyelination throughout the central nervous system of enzyme treated animals compared to placebo-treated, age-matched affected controls. Key lesions including lysosomal expansion in neurons of deep cortex, astrocytosis in cerebral cortex and medulla, and increased lysosomal membrane associated protein-1 (LAMP-1) gene expression were ameliorated in treated animals. There was no change in spheroid formation and loss of Purkinje cells, but Purkinje cell vulnerability to apoptosis was reduced with treatment. Despite reduced severity of Fucosidosis neuropathology with partial enzyme replacement, more complete and sustained biochemical correction is required to halt neuropathological processes in this large animal model of lysosomal storage disease.
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oligodendrocyte loss during the disease course in a canine model of the lysosomal storage disease Fucosidosis
Journal of Neuropathology and Experimental Neurology, 2014Co-Authors: Jessica L Fletcher, Gauthami S. Kondagari, Charles H Vite, Peter Williamson, Rosanne M. TaylorAbstract:Hypomyelination is a poorly understood feature of many neurodegenerative lysosomal storage diseases, including Fucosidosis in children and animals. To gain insight into hypomyelination in Fucosidosis, we investigated lysosomal storage, oligodendrocyte death, and axonal and neuron loss in CNS tissues of Fucosidosis-affected dogs aged 3 weeks to 42 months using immunohistochemistry, electron microscopy, and gene expression assays. Vacuole accumulation in Fucosidosis oligodendrocytes commenced by 5 weeks of age; all oligodendrocytes were affected by 16 weeks. Despite progressive vacuolation, mature oligodendrocyte loss by apoptosis (caspase-6 positive) in the corpus callosum and cerebellar white matter stabilized by 16 weeks, with no further subsequent loss. Axonal neurofilament loss progressed only in late disease, suggesting that disturbed axon-oligodendrocyte interactions are unlikely to be the primary cause of hypomyelination. A 67% decline in the number of Purkinje cell layer oligodendrocytes coincided with a 67% increase in the number of caspase-6-positive Purkinje cells at 16 weeks, suggesting that early oligodendrocyte loss contributes to Purkinje cell apoptosis. Fucosidosis hypomyelination appeared to follow normal spatiotemporal patterns of myelination, with greater loss of oligodendrocytes and larger downregulation of CNP, MAL, and PLP1 genes at 16 weeks in the cerebellum versus the frontal cortex. These studies suggest that survival of oligodendrocytes in Fucosidosis is limited during active myelination, although the mechanisms remain unknown.
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Myelin genes are downregulated in canine Fucosidosis.
Biochimica et biophysica acta, 2011Co-Authors: Jessica L Fletcher, Gauthami S. Kondagari, Peter Williamson, Amanda L. Wright, Peter C. Thomson, Rosanne M. TaylorAbstract:The processes regulating the complex neurodegenerative cascade of vacuolation, neuroinflammation, neuronal loss and myelin deficits in Fucosidosis, a neurological lysosomal storage disorder, remain unclear. To elucidate these processes the gene expression profile of the cerebral cortex from untreated and intrathecal enzyme replacement therapy treated Fucosidosis pups and age-matched unaffected controls were examined. Neuroinflammation and cell death processes were identified to have a major role in Fucosidosis pathophysiology with 37% of differentially expressed (DE) genes involved in these processes. Critical, specific, early decreases in expression levels of key genes in myelin assembly were identified by gene expression profiling, including myelin-associated glycoprotein (MAG), myelin and lymphocyte protein (MAL), and oligodendrocyte myelin paranodal and inner loop protein (OPALIN). These gene expression changes may be indicative of early neuronal loss causing reduced electrical impulses required for oligodendrocyte maturation.
Heike Wolf - One of the best experts on this subject based on the ideXlab platform.
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Sensorimotor and Neurocognitive Dysfunctions Parallel Early Telencephalic Neuropathology in Fucosidosis Mice.
Frontiers in behavioral neuroscience, 2018Co-Authors: Stijn Stroobants, Heike Wolf, Thomas Dierks, Torben Lübke, Zsuzsanna Callaerts-vegh, Rudi D'hoogeAbstract:Fucosidosis is a lysosomal storage disorder (LSD) caused by lysosomal α-L-fucosidase deficiency. Insufficient α-L-fucosidase activity triggers accumulation of undegraded, fucosylated glycoproteins and glycolipids in various tissues. The human phenotype is heterogeneous, but progressive motor and cognitive impairments represent the most characteristic symptoms. Recently, Fuca1-deficient mice were generated by gene targeting techniques, constituting a novel animal model for human Fucosidosis. These mice display widespread LSD pathology, accumulation of secondary storage material and neuroinflammation throughout the brain, as well as progressive loss of Purkinje cells. Fuca1-deficient mice and control littermates were subjected to a battery of tests detailing different aspects of motor, emotional and cognitive function. At an early stage of disease, we observed reduced exploratory activity, sensorimotor disintegration as well as impaired spatial learning and fear memory. These early markers of neurological deterioration were related to the respective stage of neuropathology using molecular genetic and immunochemical procedures. Increased expression of the lysosomal marker Lamp1 and neuroinflammation markers was observed throughout the brain, but appeared more prominent in cerebral areas in comparison to cerebellum of Fuca1-deficient mice. This is consistent with impaired behaviors putatively related to early disruptions of motor and cognitive circuits particularly involving cerebral cortex, basal ganglia, and hippocampus. Thus, Fuca1-deficient mice represent a practical and promising Fucosidosis model, which can be utilized for pathogenetic and therapeutic studies.
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A mouse model for Fucosidosis recapitulates storage pathology and neurological features of the milder form of the human disease.
Disease models & mechanisms, 2016Co-Authors: Heike Wolf, Markus Damme, Stijn Stroobants, Rudi D'hooge, Hans Christian Beck, Irm Hermans-borgmeyer, Renate Lüllmann-rauch, Thomas Dierks, Torben LübkeAbstract:Fucosidosis is a rare lysosomal storage disorder caused by the inherited deficiency of the lysosomal hydrolase α-L-fucosidase, which leads to an impaired degradation of fucosylated glycoconjugates. Here, we report the generation of a Fucosidosis mouse model, in which the gene for lysosomal α-L-fucosidase (Fuca1) was disrupted by gene targeting. Homozygous knockout mice completely lack α-L-fucosidase activity in all tested organs leading to highly elevated amounts of the core-fucosylated glycoasparagine Fuc(α1,6)-GlcNAc(β1-N)-Asn and, to a lesser extent, other fucosylated glycoasparagines, which all were also partially excreted in urine. Lysosomal storage pathology was observed in many visceral organs, such as in the liver, kidney, spleen and bladder, as well as in the central nervous system (CNS). On the cellular level, storage was characterized by membrane-limited cytoplasmic vacuoles primarily containing water-soluble storage material. In the CNS, cellular alterations included enlargement of the lysosomal compartment in various cell types, accumulation of secondary storage material and neuroinflammation, as well as a progressive loss of Purkinje cells combined with astrogliosis leading to psychomotor and memory deficits. Our results demonstrate that this new Fucosidosis mouse model resembles the human disease and thus will help to unravel underlying pathological processes. Moreover, this model could be utilized to establish diagnostic and therapeutic strategies for Fucosidosis.
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The lysosomal storage disease Fucosidosis: towards enzyme replacement therapy
2016Co-Authors: Heike WolfAbstract:Fucosidosis is a rare lysosomal storage disease caused by the deficiency of the lysosomal glycosidase a-L-fucosidase resulting in the accumulation of fucosylated glycocompounds. Human Fucosidosis patients are mainly characterized by progressive mental retardation and neurological deterioration leading to premature death. In this study, the generation of a constitutive Fucosidosis mouse model is reported. The gene for the lysosomal a-L-fucosidase (Fuca1) was disrupted by gene targeting resulting in the complete absence of a-L-fucosidase activity in Fuca1(-/-) mice. The phenotype of the mouse model closely resembled that of a milder form of the human disease and due to animal welfare, the Fuca1(-/-) mice had to be euthanized at 9 - 11 months of age. A lysosomal storage pathology was detected in nearly all investigated organs of the mouse model, e. g. in liver, kidney, spleen as well as in the CNS, and was characterized by foam-like storage vacuoles to variable degree. An immense accumulation of water-soluble fucosylated glycocompounds was demonstrated and the glycoasparagine Asn-GlcNAc-Fuc was identified as main storage material in kidney and brain and was also excreted with the urine of the Fuca1(-/-) mice. The neuropathological alterations of the mouse model were analyzed in more detail, as these are the leading symptoms in human Fucosidosis. The Fuca1(-/-) mice exhibited neuroinflammatory signs including prominent micro- and astrogliosis and suffered from progressive loss of Purkinje cells. Particularly the latter might contribute to behavioral abnormalities of the animals including progressive coordinatory and motor deficits as well as a reduced overall activity and cognitive impairment. In order to enable the development of an enzyme replacement therapy (ERT) for the Fucosidosis disease, an expression system for the production of the human a-L-fucosidase was generated in CHO-K1 cells. While a purification strategy for the His6-tagged enzyme was established using a Ni2+-affinity chromatography followed by a strong cation exchange chromatography, the purification of the untagged a-L-fucosidase was more challenging and needs further efforts. Finally, a Fuca1(-/-) mouse was intravenously treated with purified His6-tagged enzyme resulting in an efficient uptake of the recombinant a-L-fucosidase into visceral organs and in a complete clearance of storage material in the spleen. These preliminary results provide promising data with regard to develop an ERT also for human Fucosidosis patients.
Torben Lübke - One of the best experts on this subject based on the ideXlab platform.
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Sensorimotor and Neurocognitive Dysfunctions Parallel Early Telencephalic Neuropathology in Fucosidosis Mice.
Frontiers in behavioral neuroscience, 2018Co-Authors: Stijn Stroobants, Heike Wolf, Thomas Dierks, Torben Lübke, Zsuzsanna Callaerts-vegh, Rudi D'hoogeAbstract:Fucosidosis is a lysosomal storage disorder (LSD) caused by lysosomal α-L-fucosidase deficiency. Insufficient α-L-fucosidase activity triggers accumulation of undegraded, fucosylated glycoproteins and glycolipids in various tissues. The human phenotype is heterogeneous, but progressive motor and cognitive impairments represent the most characteristic symptoms. Recently, Fuca1-deficient mice were generated by gene targeting techniques, constituting a novel animal model for human Fucosidosis. These mice display widespread LSD pathology, accumulation of secondary storage material and neuroinflammation throughout the brain, as well as progressive loss of Purkinje cells. Fuca1-deficient mice and control littermates were subjected to a battery of tests detailing different aspects of motor, emotional and cognitive function. At an early stage of disease, we observed reduced exploratory activity, sensorimotor disintegration as well as impaired spatial learning and fear memory. These early markers of neurological deterioration were related to the respective stage of neuropathology using molecular genetic and immunochemical procedures. Increased expression of the lysosomal marker Lamp1 and neuroinflammation markers was observed throughout the brain, but appeared more prominent in cerebral areas in comparison to cerebellum of Fuca1-deficient mice. This is consistent with impaired behaviors putatively related to early disruptions of motor and cognitive circuits particularly involving cerebral cortex, basal ganglia, and hippocampus. Thus, Fuca1-deficient mice represent a practical and promising Fucosidosis model, which can be utilized for pathogenetic and therapeutic studies.
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A mouse model for Fucosidosis recapitulates storage pathology and neurological features of the milder form of the human disease.
Disease models & mechanisms, 2016Co-Authors: Heike Wolf, Markus Damme, Stijn Stroobants, Rudi D'hooge, Hans Christian Beck, Irm Hermans-borgmeyer, Renate Lüllmann-rauch, Thomas Dierks, Torben LübkeAbstract:Fucosidosis is a rare lysosomal storage disorder caused by the inherited deficiency of the lysosomal hydrolase α-L-fucosidase, which leads to an impaired degradation of fucosylated glycoconjugates. Here, we report the generation of a Fucosidosis mouse model, in which the gene for lysosomal α-L-fucosidase (Fuca1) was disrupted by gene targeting. Homozygous knockout mice completely lack α-L-fucosidase activity in all tested organs leading to highly elevated amounts of the core-fucosylated glycoasparagine Fuc(α1,6)-GlcNAc(β1-N)-Asn and, to a lesser extent, other fucosylated glycoasparagines, which all were also partially excreted in urine. Lysosomal storage pathology was observed in many visceral organs, such as in the liver, kidney, spleen and bladder, as well as in the central nervous system (CNS). On the cellular level, storage was characterized by membrane-limited cytoplasmic vacuoles primarily containing water-soluble storage material. In the CNS, cellular alterations included enlargement of the lysosomal compartment in various cell types, accumulation of secondary storage material and neuroinflammation, as well as a progressive loss of Purkinje cells combined with astrogliosis leading to psychomotor and memory deficits. Our results demonstrate that this new Fucosidosis mouse model resembles the human disease and thus will help to unravel underlying pathological processes. Moreover, this model could be utilized to establish diagnostic and therapeutic strategies for Fucosidosis.
