Decreased neural stem cell proliferation and olfaction in mouse models of Niemann–Pick C1 disease and the response to hydroxypropyl-β-cyclodextrin
- 44 Downloads
The Npc1nih/nih-null model and the Npc1nmf164/nmf164 hypomorph models of Niemann–Pick C1 (NPC1) disease show defects in olfaction. We have tested the effects of the life-prolonging treatment hydroxypropyl-beta-cyclodextrin (HPBCD) on olfaction and neural stem cell numbers when delivered either systemically or by nasal inhalation. Using the paradigm of finding a hidden cube of food after overnight food deprivation, Npc1nih/nih homozygous mice showed a highly significant delay in finding the food compared with wild-type mice. Npc1nmf164/nmf164 homozygous mice showed an early loss of olfaction which was mildly corrected by somatic delivery of HPBCD which also increased the number of neural stem cells in the mutant but did not change the number in wild-type mice. In contrast, nasal delivery of this drug, at 1/5 the dosage used for somatic delivery, to Npc1nmf164/nmf164 mutant mice delayed loss of olfaction but the control of nasal delivered saline did so as well. The nasal delivery of HPBCD to wild-type mice caused loss of olfaction but nasal delivery of saline did not. Neural stem cell counts were not improved by nasal therapy with HPBCD. We credit the delay in olfaction found with the treatment, a delay which was also found for time of death, to a large amount of stimulation the mice received with handling during the nasal delivery.
KeywordsOlfaction Niemann–Pick C1 disease Hydroxypropyl-beta-cyclodextrins Neural stem cells Nasal delivery
RPE acknowledges the support of the University Roma, La Sapienza for visiting research professorships.
J. D. and G. P. performed BrdU labelling, immunohistochemistry, and treatments; G. P. and P. C. performed olfactory testing; S. C. performed HPBCD treatments and supervised experiments; M. T. F. and R. P. E. conceived the study and wrote the manuscript.
The financial supports of Telethon Foundation - Italy (grant no. GGP13183 to M.T.F.) and the Ateneo La Sapienza (RM11615501ED6577) are gratefully acknowledged.
Compliance with ethical standards
Experimental protocols and related procedures were approved by the University of Arizona IACUC Institutional Animal Care Utilization Committee and Italian Ministry of Public Health. All experiments were conducted according to the Italia law DL 26/2014 on the protection of animals used for scientific purpose.
Conflict of interest
The authors declare that they have no competing interests.
- Alvarez-Buylla A, Garcia-Verdugo JM (2002) Neurogenesis in adult subventricular zone. J Neurosci 22:629–634. https://doi.org/10.1523/JNEUROSCI.22-03-00629.2002 CrossRefPubMedPubMedCentralGoogle Scholar
- Caporali P, Bruno F, Palladino G, Dragotto J, Petrosini L, Mangia F, Erickson RP, Canterini S, Fiorenza MT (2016) Developmental delay in motor skill acquisition in Niemann-Pick C1 mice reveals abnormal cerebellar morphogenesis. Acta Neuropathol Commun 4:94. https://doi.org/10.1186/s40478-016-0370-z CrossRefPubMedPubMedCentralGoogle Scholar
- Davidson CD, Ali NF, Micsenyi MC, Stephney G, Renault S, Dobrenis K, Ory DS, Vanier MT, Walkley SU (2009) Chronic cyclodextrin treatment of murine Niemann-Pick C disease ameliorates neuronal cholesterol and glycosphingolipid storage and disease progression. PLoS One 4:e6951. https://doi.org/10.1371/journal.pone.0006951 CrossRefPubMedPubMedCentralGoogle Scholar
- Erickson RP, Deutsch G, Patil R (2018) A pilot study of direct delivery of hydroxypropyl-beta-cyclodextrin to the lung by the nasal route in a mouse model of Niemann-Pick C1 disease: motor performance is unaltered and lung disease is worsened. J Appl Genet 59:187–191. https://doi.org/10.1007/s13353-018-0431-z CrossRefPubMedGoogle Scholar
- Garver WS, Jelinek D, Meaney FJ, Flynn J, Pettit KM, Shepherd G, Heidenreich RA, Vockley CM, Castro G, Francis GA (2010) The National Niemann-Pick Type C1 Disease Database: correlation of lipid profiles, mutations, and biochemical phenotypes. J Lipid Res 51:406–415. https://doi.org/10.1194/jlr.P000331 CrossRefGoogle Scholar
- Kulaga HM, Leitch CC, Eichers ER, Badano JL, Lesemann A, Hoskins BE, Lupski JR, Beales PL, Reed RR, Katsanis N (2004) Loss of BBS proteins causes anosmia in humans and defects in olfactory cilia structure and function in the mouse. Nat Genet 36:994. https://doi.org/10.1038/ng1418 CrossRefPubMedGoogle Scholar
- Liu B, Ramirez CM, Miller AM, Repa JJ, Turley SD, Dietschy JM (2010) Cyclodextrin overcomes the transport defect in nearly every organ of NPC1 mice leading to excretion of sequestered cholesterol as bile acid. J Lipid Res 51:933–944. https://doi.org/10.1194/jlr.M000257 CrossRefPubMedPubMedCentralGoogle Scholar
- Luskin MB (1998) Neuroblasts of the postnatal mammalian forebrain: their phenotype and fate. J Neurobiol 36:221–233. https://doi.org/10.1002/(SICI)1097-4695(199808)36:2-221 CrossRefPubMedGoogle Scholar
- Marshall CA, Watkins-Chow DE, Palladino G, Deutsch G, Chandran K, Pavan WJ, Erickson RP (2018) In Niemann-Pick C1 mouse models, glial-only expression of the normal gene extends survival much further than do changes in genetic background or treatment with hydroxypropyl-beta-cyclodextrin. Gene 643:117–123. https://doi.org/10.1016/j.gene.2017.12.006 CrossRefPubMedGoogle Scholar
- Maue RA, Burgess RW, Wang B, Wooley CM, Seburn KA, Vanier MR, Rogers MA, Chang CC, Chang T-Y, Harris BT, Graber DJ, Penatti CAA, Porter DM, Szwergold BS, Henderson LP, Totenhagen JW, Trouard TP, Borbon IA, Erickson RP (2011) A novel mouse model of Niemann–Pick type C disease carrying a D1005G-Npc1 mutation comparable to commonly observed human mutations. Hum Mol Genet 21:730–750. https://doi.org/10.1093/hmg/ddr505 CrossRefPubMedPubMedCentralGoogle Scholar
- Nusca S, Canterini S, Palladino G, Bruno F, Mangia F, Erickson RP, Fiorenza MT (2014) A marked paucity of granule cells in the developing cerebellum of the Npc1−/− mouse is corrected by a single injection of hydroxypropyl-β-cyclodextrin. Neurobiol Dis 70:117–126. https://doi.org/10.1016/j.nbd.2014.06.012 CrossRefPubMedPubMedCentralGoogle Scholar
- Palladino G, Loizzo S, Fortuna A, Canterini S, Palombi F, Erickson RP, Mangia F, Fiorenza MT (2015) 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 J Rare Dis 10:133. https://doi.org/10.1186/s13023-015-0348-0 CrossRefPubMedPubMedCentralGoogle Scholar
- Park MH, Choi BJ, Jeong MS, Lee JY, Jung IK, Park KH, Lee HW, Yamaguchi T, Marti HH, Lee BH, Schuchman EH, Jin HK, Bae J-S (2019) Characterization of the subventricular-thalmo-cortical circuit in the NP-C mouse brain, and new insights regarding treatment. Mol Ther. https://doi.org/10.1016/j.mthe.2019.06.008
- Patterson MC, Vanier MT, Suzuki K, Morris JA, Carstea E, Neufeld EB, Blanchette-Mackie JE, Pentchev PG (2001) Niemann–Pick disease C: a lipid trafficking disorder. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease, vol III, 8th edn. McGraw-Hill, New York, pp 3611–3633Google Scholar
- Seo Y, Kim H-S, Shin Y, Kang I, Choi SW, Yu K-R, Seo K-W, Kang K-S (2014) Excessive microglial activation aggravates olfactory dysfunction by impeding the survival of newborn neurons in the olfactory bulb of Niemann–Pick disease type C1 mice. Biochim Biophys Acta (BBA)-Mol Basis Dis 1842:2193–2203. https://doi.org/10.1016/j.bbadis CrossRefGoogle Scholar
- Seo Y, Kim H-S, Kang I, Choi SW, Shin T-H, Shin J-H, Lee B-C, Lee JY, Kim J-J, Kook MG, Kang K-S (2016) Cathepsin S contributes to microglia-mediated olfactory dysfunction through the regulation of C x3cl1–C x3cr1 axis in a N iemann–Pick disease type C 1 model. Glia 64:2291–2305. https://doi.org/10.1002/glia.23077 CrossRefPubMedGoogle Scholar