Miglustat Reverts the Impairment of Synaptic Plasticity in a Mouse Model of NPC Disease
Niemann-Pick type C disease is an autosomal recessive storage disorder, characterized by abnormal sequestration of unesterified cholesterol within the late endolysosomal compartment of cells and accumulation of gangliosides and other sphingolipids. Progressive neurological deterioration and insurgen...
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| Format: | Article |
| Language: | English |
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Wiley
2016-01-01
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| Series: | Neural Plasticity |
| Online Access: | http://dx.doi.org/10.1155/2016/3830424 |
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| author | G. D’Arcangelo D. Grossi M. Racaniello A. Cardinale A. Zaratti S. Rufini A. Cutarelli V. Tancredi D. Merlo C. Frank |
| author_facet | G. D’Arcangelo D. Grossi M. Racaniello A. Cardinale A. Zaratti S. Rufini A. Cutarelli V. Tancredi D. Merlo C. Frank |
| author_sort | G. D’Arcangelo |
| collection | DOAJ |
| description | Niemann-Pick type C disease is an autosomal recessive storage disorder, characterized by abnormal sequestration of unesterified cholesterol within the late endolysosomal compartment of cells and accumulation of gangliosides and other sphingolipids. Progressive neurological deterioration and insurgence of symptoms like ataxia, seizure, and cognitive decline until severe dementia are pathognomonic features of the disease. Here, we studied synaptic plasticity phenomena and evaluated ERKs activation in the hippocampus of BALB/c NPC1−/− mice, a well described animal model of the disease. Our results demonstrated an impairment of both induction and maintenance of long term synaptic potentiation in NPC1−/− mouse slices, associated with the lack of ERKs phosphorylation. We then investigated the effects of Miglustat, a recent approved drug for the treatment of NPCD. We found that in vivo Miglustat administration in NPC1−/− mice was able to rescue synaptic plasticity deficits, to restore ERKs activation and to counteract hyperexcitability. Overall, these data indicate that Miglustat may be effective for treating the neurological deficits associated with NPCD, such as seizures and dementia. |
| format | Article |
| id | doaj-art-33fd4f95ba42426081365920c84edf86 |
| institution | Kabale University |
| issn | 2090-5904 1687-5443 |
| language | English |
| publishDate | 2016-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Neural Plasticity |
| spelling | doaj-art-33fd4f95ba42426081365920c84edf862025-02-03T01:32:02ZengWileyNeural Plasticity2090-59041687-54432016-01-01201610.1155/2016/38304243830424Miglustat Reverts the Impairment of Synaptic Plasticity in a Mouse Model of NPC DiseaseG. D’Arcangelo0D. Grossi1M. Racaniello2A. Cardinale3A. Zaratti4S. Rufini5A. Cutarelli6V. Tancredi7D. Merlo8C. Frank9Department of Medical System, University of Rome Tor Vergata, 00133 Rome, ItalyDepartment of Medical System, University of Rome Tor Vergata, 00133 Rome, ItalyDepartment of Cell Biology and Neuroscience, Istituto Superiore di Sanità, 00161 Rome, ItalyIRCCS San Raffaele Pisana, 00163 Rome, ItalyDepartment of Biology, University of Rome Tor Vergata, 00133 Rome, ItalyDepartment of Biology, University of Rome Tor Vergata, 00133 Rome, ItalyNational Centre for Rare Diseases, Istituto Superiore di Sanità, 00161 Rome, ItalyDepartment of Medical System, University of Rome Tor Vergata, 00133 Rome, ItalyDepartment of Cell Biology and Neuroscience, Istituto Superiore di Sanità, 00161 Rome, ItalyNational Centre for Rare Diseases, Istituto Superiore di Sanità, 00161 Rome, ItalyNiemann-Pick type C disease is an autosomal recessive storage disorder, characterized by abnormal sequestration of unesterified cholesterol within the late endolysosomal compartment of cells and accumulation of gangliosides and other sphingolipids. Progressive neurological deterioration and insurgence of symptoms like ataxia, seizure, and cognitive decline until severe dementia are pathognomonic features of the disease. Here, we studied synaptic plasticity phenomena and evaluated ERKs activation in the hippocampus of BALB/c NPC1−/− mice, a well described animal model of the disease. Our results demonstrated an impairment of both induction and maintenance of long term synaptic potentiation in NPC1−/− mouse slices, associated with the lack of ERKs phosphorylation. We then investigated the effects of Miglustat, a recent approved drug for the treatment of NPCD. We found that in vivo Miglustat administration in NPC1−/− mice was able to rescue synaptic plasticity deficits, to restore ERKs activation and to counteract hyperexcitability. Overall, these data indicate that Miglustat may be effective for treating the neurological deficits associated with NPCD, such as seizures and dementia.http://dx.doi.org/10.1155/2016/3830424 |
| spellingShingle | G. D’Arcangelo D. Grossi M. Racaniello A. Cardinale A. Zaratti S. Rufini A. Cutarelli V. Tancredi D. Merlo C. Frank Miglustat Reverts the Impairment of Synaptic Plasticity in a Mouse Model of NPC Disease Neural Plasticity |
| title | Miglustat Reverts the Impairment of Synaptic Plasticity in a Mouse Model of NPC Disease |
| title_full | Miglustat Reverts the Impairment of Synaptic Plasticity in a Mouse Model of NPC Disease |
| title_fullStr | Miglustat Reverts the Impairment of Synaptic Plasticity in a Mouse Model of NPC Disease |
| title_full_unstemmed | Miglustat Reverts the Impairment of Synaptic Plasticity in a Mouse Model of NPC Disease |
| title_short | Miglustat Reverts the Impairment of Synaptic Plasticity in a Mouse Model of NPC Disease |
| title_sort | miglustat reverts the impairment of synaptic plasticity in a mouse model of npc disease |
| url | http://dx.doi.org/10.1155/2016/3830424 |
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