Visual evoked potentials of Niemann-Pick type C1 mice reveal an impairment of the visual pathway that is rescued by 2-hydroxypropyl-ẞ-cyclodextrin

Persistent Link:
http://hdl.handle.net/10150/610327
Title:
Visual evoked potentials of Niemann-Pick type C1 mice reveal an impairment of the visual pathway that is rescued by 2-hydroxypropyl-ẞ-cyclodextrin
Author:
Palladino, G.; Loizzo, S.; Fortuna, A.; Canterini, S.; Palombi, F.; Erickson, R. P.; Mangia, F.; Fiorenza, M. T.
Affiliation:
Department of Psychology, Section of Neuroscience and "Daniel Bovet" Neurobiology Research Center, Sapienza University of Rome; Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità; Department of Anatomy, Histology, Forensic Medicine and Orthopedics, Unit of Histology and Medical Embryology, Sapienza University of Rome; Department of Pediatrics, University of Arizona
Issue Date:
2015
Publisher:
BioMed Central
Citation:
Palladino et al. Orphanet Journal of Rare Diseases (2015) 10:133 DOI 10.1186/s13023-015-0348-0
Journal:
Orphanet Journal of Rare Diseases
Rights:
© 2015 Palladino et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/)
Collection Information:
This item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at repository@u.library.arizona.edu.
Abstract:
BACKGROUND: The lysosomal storage disorder, Niemann Pick type C1 (NPC1), presents a variable phenotype including neurovisceral and neurological symptoms. 2-Hydroxypropyl-ss-cyclodextrin (HPssCD)-based therapies are presently the most promising route of intervention. While severe cerebellar dysfunction remains the main disabling feature of NPC1, sensory functions including auditory and olfactory ones are also affected. Morphological and functional anomalies of Npc1 (-/-) mouse retina have also been observed, although the functional integrity of the visual pathway from retina to visual cortex is still unsettled. We have addressed this issue by characterizing the visual evoked potential (VEP) response of Npc1 (-/-) mice and determining if/how HPssCD administration influences the VEPs of both Npc1 (-/-) and Npc1 (+/+) mice. METHODS: VEP elicited by a brief visual stimulus were recorded from the scalp overlying the visual cortex of adult (PN, postnatal days 60, 75, 85 and 100) Npc1 (+/+) and Npc1 (-/-) mice that had received repeated injections of either HPssCD or plain vehicle. The first injection was given at PN4 and was followed by a second one at PN7 and thereafter by weekly injections up to PN49. Cholesterol accumulation and myelin loss were finally assessed by filipin staining and myelin basic protein immunohistochemistry, respectively. RESULTS AND DISCUSSION: We have found that the transmission of visual signals from retina to visual cortex is negatively influenced by the loss of Npc1 function. In fact, the VEP response of Npc1 (-/-) mice displayed a highly significant increase in the latency compared to that of Npc1 (+/+) mice. HPssCD administration fully rescued this defect and counteracted the cholesterol accumulation in retinal ganglion cells and dorsal lateral geniculate nucleus neurons, as well as the myelin loss in optic nerve fibers and axons projecting to the visual cortex observed in of Npc1 (-/-) mice. By contrast, HPssCD administration had no effect on the VEP response of Npc1 (+/+) mice, further strengthening the treatment efficacy. CONCLUSIONS: This study pinpoints the analysis of VEP response as a potentially accurate and non-invasive approach to assess neural activity and visual information processing in NPC1 patients, as well as for monitoring the progression of the disease and assessing the efficacy of potential therapies.
EISSN:
1750-1172
PubMed ID:
26458950
PubMed Central ID:
PMC4603821
DOI:
10.1186/s13023-015-0348-0 [doi]
Keywords:
Lysosomal diseases; Rare disease; Npc1; HPßCD; Cholesterol; Neurodegeneration; Dysmyelination
Version:
Final published version
Additional Links:
http://www.ojrd.com/content/10/1/133

Full metadata record

DC FieldValue Language
dc.contributor.authorPalladino, G.en
dc.contributor.authorLoizzo, S.en
dc.contributor.authorFortuna, A.en
dc.contributor.authorCanterini, S.en
dc.contributor.authorPalombi, F.en
dc.contributor.authorErickson, R. P.en
dc.contributor.authorMangia, F.en
dc.contributor.authorFiorenza, M. T.en
dc.date.accessioned2016-05-20T09:04:17Z-
dc.date.available2016-05-20T09:04:17Z-
dc.date.issued2015en
dc.identifier.citationPalladino et al. Orphanet Journal of Rare Diseases (2015) 10:133 DOI 10.1186/s13023-015-0348-0en
dc.identifier.pmid26458950en
dc.identifier.doi10.1186/s13023-015-0348-0 [doi]en
dc.identifier.urihttp://hdl.handle.net/10150/610327-
dc.description.abstractBACKGROUND: The lysosomal storage disorder, Niemann Pick type C1 (NPC1), presents a variable phenotype including neurovisceral and neurological symptoms. 2-Hydroxypropyl-ss-cyclodextrin (HPssCD)-based therapies are presently the most promising route of intervention. While severe cerebellar dysfunction remains the main disabling feature of NPC1, sensory functions including auditory and olfactory ones are also affected. Morphological and functional anomalies of Npc1 (-/-) mouse retina have also been observed, although the functional integrity of the visual pathway from retina to visual cortex is still unsettled. We have addressed this issue by characterizing the visual evoked potential (VEP) response of Npc1 (-/-) mice and determining if/how HPssCD administration influences the VEPs of both Npc1 (-/-) and Npc1 (+/+) mice. METHODS: VEP elicited by a brief visual stimulus were recorded from the scalp overlying the visual cortex of adult (PN, postnatal days 60, 75, 85 and 100) Npc1 (+/+) and Npc1 (-/-) mice that had received repeated injections of either HPssCD or plain vehicle. The first injection was given at PN4 and was followed by a second one at PN7 and thereafter by weekly injections up to PN49. Cholesterol accumulation and myelin loss were finally assessed by filipin staining and myelin basic protein immunohistochemistry, respectively. RESULTS AND DISCUSSION: We have found that the transmission of visual signals from retina to visual cortex is negatively influenced by the loss of Npc1 function. In fact, the VEP response of Npc1 (-/-) mice displayed a highly significant increase in the latency compared to that of Npc1 (+/+) mice. HPssCD administration fully rescued this defect and counteracted the cholesterol accumulation in retinal ganglion cells and dorsal lateral geniculate nucleus neurons, as well as the myelin loss in optic nerve fibers and axons projecting to the visual cortex observed in of Npc1 (-/-) mice. By contrast, HPssCD administration had no effect on the VEP response of Npc1 (+/+) mice, further strengthening the treatment efficacy. CONCLUSIONS: This study pinpoints the analysis of VEP response as a potentially accurate and non-invasive approach to assess neural activity and visual information processing in NPC1 patients, as well as for monitoring the progression of the disease and assessing the efficacy of potential therapies.en
dc.language.isoenen
dc.publisherBioMed Centralen
dc.relation.urlhttp://www.ojrd.com/content/10/1/133en
dc.rights© 2015 Palladino et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/)en
dc.subjectLysosomal diseasesen
dc.subjectRare diseaseen
dc.subjectNpc1en
dc.subjectHPßCDen
dc.subjectCholesterolen
dc.subjectNeurodegenerationen
dc.subjectDysmyelinationen
dc.titleVisual evoked potentials of Niemann-Pick type C1 mice reveal an impairment of the visual pathway that is rescued by 2-hydroxypropyl-ẞ-cyclodextrinen
dc.typeArticleen
dc.identifier.eissn1750-1172en
dc.contributor.departmentDepartment of Psychology, Section of Neuroscience and "Daniel Bovet" Neurobiology Research Center, Sapienza University of Romeen
dc.contributor.departmentDepartment of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanitàen
dc.contributor.departmentDepartment of Anatomy, Histology, Forensic Medicine and Orthopedics, Unit of Histology and Medical Embryology, Sapienza University of Romeen
dc.contributor.departmentDepartment of Pediatrics, University of Arizonaen
dc.identifier.journalOrphanet Journal of Rare Diseasesen
dc.identifier.pmcidPMC4603821en
dc.description.collectioninformationThis item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at repository@u.library.arizona.edu.en
dc.eprint.versionFinal published versionen

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