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

Orphanet Journal of Rare Diseases

Maria Teresa Fiorenza³  Franco Mangia³  Robert P. Erickson¹  Fioretta Palombi²  Sonia Canterini³  Andrea Fortuna⁴  Stefano Loizzo⁴  Giampiero Palladino³ 

[1] Department of Pediatrics, University of Arizona, Tucson 85724-5073, AZ, USA;Department of Anatomy, Histology, Forensic Medicine and Orthopedics, Unit of Histology and Medical Embryology, Sapienza University of Rome, Rome, 00161, Italy;Department of Psychology, Section of Neuroscience and “Daniel Bovet” Neurobiology Research Center, Sapienza University of Rome, Rome, 00185, Italy;Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, via Regina Elena 299, Rome, 00161, Italy

关键词: Dysmyelination;    Neurodegeneration;    Cholesterol;    HPßCD;    Npc1;    Rare disease;    Lysosomal diseases;   

Others  :  1228800
DOI  :  10.1186/s13023-015-0348-0

 received in 2015-05-12, accepted in 2015-09-27,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Palladino et al.

【 图 表 】

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