Enhanced degradation of synaptophysin by the proteasome in mucopolysaccharidosis type IIIB

Vitry, Sandrine; Ausseil, Jérôme; Hocquemiller, Michaël; Bigou, Stéphanie; Coura, Renata dos Santos; Heard, Jean Michel

doi:10.1016/j.mcn.2009.01.001

Cited by 37 publications

(32 citation statements)

References 47 publications

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“…It has been shown that MPSI, IIIA and IIIB mouse brains exhibit primary storage of HS, secondary accumulation of GM2 and 3 gangliosides and severe neuroinflammation [6], [21], [22], [23], [24], [25], but these parameters have never been fully quantified so that direct comparisons could be made between these three sub-types in detail. Changes in the level of synaptic proteins, vesicle associated membrane protein 2 (VAMP2 or synaptobrevin 2) and synaptophysin, have been observed in MPSIIIB mice, which may result in altered downstream synaptic signalling events [8], [26], [27], but this has not been shown for MPSI and MPSIIIA. Alterations in the levels of synaptic proteins may result in behavioural changes and ultimately neurodegeneration.…”

Section: Introductionmentioning

confidence: 99%

Neuropathology in Mouse Models of Mucopolysaccharidosis Type I, IIIA and IIIB

et al. 2012

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Mucopolysaccharide diseases (MPS) are caused by deficiency of glycosaminoglycan (GAG) degrading enzymes, leading to GAG accumulation. Neurodegenerative MPS diseases exhibit cognitive decline, behavioural problems and shortened lifespan. We have characterised neuropathological changes in mouse models of MPSI, IIIA and IIIB to provide a better understanding of these events.Wild-type (WT), MPSI, IIIA and IIIB mouse brains were analysed at 4 and 9 months of age. Quantitative immunohistochemistry showed significantly increased lysosomal compartment, GM2 ganglioside storage, neuroinflammation, decreased and mislocalised synaptic vesicle associated membrane protein, (VAMP2), and decreased post-synaptic protein, Homer-1, in layers II/III-VI of the primary motor, somatosensory and parietal cortex. Total heparan sulphate (HS), was significantly elevated, and abnormally N-, 6-O and 2-O sulphated compared to WT, potentially altering HS-dependent cellular functions. Neuroinflammation was confirmed by significantly increased MCP-1, MIP-1α, IL-1α, using cytometric bead arrays. An overall genotype effect was seen in all parameters tested except for synaptophysin staining, neuronal cell number and cortical thickness which were not significantly different from WT. MPSIIIA and IIIB showed significantly more pronounced pathology than MPSI in lysosomal storage, astrocytosis, microgliosis and the percentage of 2-O sulphation of HS. We also observed significant time progression of all genotypes from 4–9 months in lysosomal storage, astrocytosis, microgliosis and synaptic disorganisation but not GM2 gangliosidosis. Individual genotype*time differences were disparate, with significant progression from 4 to 9 months only seen for MPSIIIB with lysosomal storage, MPSI with astrocytocis and MPSIIIA with microgliosis as well as neuronal loss. Transmission electron microscopy of MPS brains revealed dystrophic axons, axonal storage, and extensive lipid and lysosomal storage. These data lend novel insight to MPS neuropathology, suggesting that MPSIIIA and IIIB have more pronounced neuropathology than MPSI, yet all are still progressive, at least in some aspects of neuropathology, from 4–9 months.

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Section: Introductionmentioning

confidence: 99%

Neuropathology in Mouse Models of Mucopolysaccharidosis Type I, IIIA and IIIB

et al. 2012

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“…MPS III children present typically with developmental delay that can be accompanied by severe hyperactivity, autistic-like social behaviors and insomnia. In animal models of MPS III, the appearance of abnormal neurological behaviors precedes neuronal cell loss and nervous system atrophy1415. This observation suggests that changes in neuronal circuit function may give rise to neurological dysfunction at disease onset.…”

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confidence: 99%

Neurodevelopmental Changes in Excitatory Synaptic Structure and Function in the Cerebral Cortex of Sanfilippo Syndrome IIIA Mice

Dwyer

Scudder

Lin

et al. 2017

Sci Rep

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Sanfilippo syndrome, MPS IIIA-D, results from deficits in lysosomal enzymes that specifically degrade heparan sulfate, a sulfated glycosaminoglycan. The accumulation of heparan sulfate results in neurological symptoms, culminating in extensive neurodegeneration and early death. To study the impact of storage in postnatal neurodevelopment, we examined murine models of MPS IIIA, which lack the enzyme sulfamidase. We show that changes occur in excitatory postsynaptic structure and function in the somatosensory cortex prior to signs of neurodegeneration. These changes coincide with accumulation of heparan sulfate with characteristic non-reducing ends, which is present at birth in the mutant mice. Accumulation of heparan sulfate was also detected in primary cultures of cortical neural cells, especially astrocytes. Accumulation of heparan sulfate in cultured astrocytes corresponded with augmented extracellular heparan sulfate and glypican 4 levels. Heparan sulfate from the cerebral cortex of MPS IIIA mice showed enhanced ability to increase glutamate AMPA receptor subunits at the cell surface of wild type neurons. These data support the idea that abnormalities in heparan sulfate content and distribution contribute to alterations in postsynaptic function. Our findings identify a disease-induced developmental phenotype that temporally overlaps with the onset of behavioral changes in a mouse model of MPS IIIA.

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“…[31][32][33][34] The clinical features of Sanfilippo syndrome, including the significant CNS component (brain and spinal cord), result from the progressive lysosomal accumulation of the GAG heparan sulfate. [35] A prevalence of mucopolysaccharidosis IIIA was cited of one in 114,000 live births and the prevalence of mucopolysaccharidosis IIIB as one in 211,000 live births. Mucopolysaccharidosis IIIC and mucopolysaccharidosis IIID were much rarer, at one in 1,407,000 and one in 1,056,000 live births, respectively.…”

Section: Mucopolysaccharidosis Type IIImentioning

confidence: 99%

Otolaryngological findings in mucopolysaccharidosis

Cingi¹

2014

J Med Updates

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Enhanced degradation of synaptophysin by the proteasome in mucopolysaccharidosis type IIIB

Cited by 37 publications

References 47 publications

Neuropathology in Mouse Models of Mucopolysaccharidosis Type I, IIIA and IIIB

Neuropathology in Mouse Models of Mucopolysaccharidosis Type I, IIIA and IIIB

Neurodevelopmental Changes in Excitatory Synaptic Structure and Function in the Cerebral Cortex of Sanfilippo Syndrome IIIA Mice

Otolaryngological findings in mucopolysaccharidosis

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