Visual evoked potentials of Niemann-Pick type C1 mice reveal an impairment of the visual pathway that is rescued by 2-hydroxypropyl-ß-cyclodextrin. Issue 1 (December 2015)

• Record Type: Journal Article
• Authors: Palladino, Giampiero; Loizzo, Stefano; Fortuna, Andrea; Canterini, Sonia; Palombi, Fioretta; Erickson, Robert; Mangia, Franco; Fiorenza, Maria
• Is Part Of: Orphanet journal of rare diseases. Volume 9:Issue 1(2014)
• Page Start: 1
• Page End: 12
• Publication Date: 2015-12
• Subjects: Lysosomal diseases -- Rare disease -- Npc1 -- HPßCD -- Cholesterol -- Neurodegeneration -- Dysmyelination; Rare diseases -- Periodicals; Genetic disorders -- Periodicals; Orphan drugs -- Periodicals; 616
• DOI: 10.1186/s13023-015-0348-0
• Languages: English
• ISSNs: 1750-1172

Abstract

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 ofNpc1 −/− 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 ofNpc1 −/− mice and determining if/how HPßCD administration influences the VEPs of bothNpc1 −/− andNpc1 +/+ 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 +/+ andNpc1 −/− 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 ofNpc1 function. In fact, the VEP response ofNpc1 −/− mice displayed a highly significant increase in the latency compared to that ofNpc1 +/+ 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 ofNpc1 −/− mice. By contrast, HPßCD administration had no effect on the VEP response ofNpc1 +/+ 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.