Early defects in mucopolysaccharidosis type IIIC disrupt excitatory synaptic transmission
Autor: | Carlos R. Morales, Jean-Claude Lacaille, Erika Freemantle, Chanshuai Han, Camila Pará, Graziella Di Cristo, Claire O'Leary, Pierre Thibault, Mahsa Taherzadeh, Brian W. Bigger, Poulomee Bose, Xuefang Pan, Peter S. McPherson, Luigi Bruno, Eric Bonneil, Alexey V. Pshezhetsky |
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Rok vydání: | 2020 |
Předmět: |
Dendritic spine
Biology Neurotransmission Inhibitory postsynaptic potential Synaptic vesicle Hippocampus Synaptic Transmission 03 medical and health sciences Mice Mucopolysaccharidosis III 0302 clinical medicine Postsynaptic potential Drug Discovery Genetics Animals Cognitive Dysfunction Cells Cultured 030304 developmental biology 0303 health sciences Mucopolysaccharidosis Type IIIC Behavior Animal Pyramidal Cells Secretory Vesicles Neurodegenerative Diseases General Medicine Lysosomal Storage Diseases Protein Transport 030220 oncology & carcinogenesis Synapses Excitatory postsynaptic potential Axoplasmic transport Disease Progression Lysosomes Neuroscience Research Article |
Zdroj: | JCI Insight |
ISSN: | 2379-3708 |
Popis: | The majority of patients affected with lysosomal storage disorders (LSD) exhibit neurological symptoms. For mucopolysaccharidosis type IIIC (MPSIIIC), the major burdens are progressive and severe neuropsychiatric problems and dementia, primarily thought to stem from neurodegeneration. Using the MPSIIIC mouse model, we studied whether clinical manifestations preceding massive neurodegeneration arise from synaptic dysfunction. Reduced levels or abnormal distribution of multiple synaptic proteins were revealed in cultured hippocampal and CA1 pyramidal MPSIIIC neurons. These defects were rescued by virus-mediated gene correction. Dendritic spines were reduced in pyramidal neurons of mouse models of MPSIIIC and other (Tay-Sachs, sialidosis) LSD as early as at P10. MPSIIIC neurons also presented alterations in frequency and amplitude of miniature excitatory and inhibitory postsynaptic currents, sparse synaptic vesicles, reduced postsynaptic densities, disorganized microtubule networks, and partially impaired axonal transport of synaptic proteins. Furthermore, postsynaptic densities were reduced in postmortem cortices of human MPS patients, suggesting that the pathology is a common hallmark for neurological LSD. Together, our results demonstrate that lysosomal storage defects cause early alterations in synaptic structure and abnormalities in neurotransmission originating from impaired synaptic vesicular transport, and they suggest that synaptic defects could be targeted to treat behavioral and cognitive defects in neurological LSD patients. |
Databáze: | OpenAIRE |
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