nach oben

Erschienen in:

05.07.2016 | Original Paper

Choline Ameliorates Disease Phenotypes in Human iPSC Models of Rett Syndrome

verfasst von: Eunice W. M. Chin, Guillaume Marcy, Su-In Yoon, Dongliang Ma, Francisco J. Rosales, George J. Augustine, Eyleen L. K. Goh

Erschienen in: NeuroMolecular Medicine | Ausgabe 3/2016

Einloggen, um Zugang zu erhalten

Abstract

Rett syndrome (RTT) is a postnatal neurodevelopmental disorder that primarily affects girls. Mutations in the methyl-CpG-binding protein 2 (MECP2) gene account for approximately 95 % of all RTT cases. To model RTT in vitro, we generated induced pluripotent stem cells (iPSCs) from fibroblasts of two RTT patients with different mutations (MECP2 ^R306C and MECP2 ^1155Δ32) in their MECP2 gene. We found that these iPSCs were capable of differentiating into functional neurons. Compared to control neurons, the RTT iPSC-derived cells had reduced soma size and a decreased amount of synaptic input, evident both as fewer Synapsin 1-positive puncta and a lower frequency of spontaneous excitatory postsynaptic currents. Supplementation of the culture media with choline rescued all of these defects. Choline supplementation may act through changes in the expression of choline acetyltransferase, an important enzyme in cholinergic signaling, and also through alterations in the lipid metabolite profiles of the RTT neurons. Our study elucidates the possible mechanistic pathways for the effect of choline on human RTT cell models, thereby illustrating the potential for using choline as a nutraceutical to treat RTT.

Amir, R. E., Van den Veyver, I. B., Schultz, R., Malicki, D. M., Tran, C. Q., Dahle, E. J., et al. (2000). Influence of mutation type and X chromosome inactivation on Rett syndrome phenotypes. Annals of Neurology, 47, 670–679.CrossRefPubMed

Amir, R. E., Van den Veyver, I. B., Wan, M., Tran, C. Q., Francke, U., & Zoghbi, H. Y. (1999). Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nature Genetics, 23, 185–188.CrossRefPubMed

Antony, A. C. (2007). In utero physiology: Role of folic acid in nutrient delivery and fetal development. American Journal of Clinical Nutrition, 85, 598S–603S.PubMed

Armstrong, D. D. (2005). Neuropathology of Rett syndrome. Journal of Child Neurology, 20, 747–753.CrossRefPubMed

Baburina, I., & Jackowski, S. (1999). Cellular responses to excess phospholipid. Journal of Biological Chemistry, 274, 9400–9408.CrossRefPubMed

Bauman, M. L., Kemper, T. L., & Arin, D. M. (1995). Pervasive neuroanatomic abnormalities of the brain in three cases of Rett’s syndrome. Neurology, 45, 1581–1586.CrossRefPubMed

Bienvenu, T., Carrie, A., de Roux, N., Vinet, M. C., Jonveaux, P., Couvert, P., et al. (2000). MECP2 mutations account for most cases of typical forms of Rett syndrome. Human Molecular Genetics, 9, 1377–1384.CrossRefPubMed

Blue, M. E., Naidu, S., & Johnston, M. V. (1999). Altered development of glutamate and GABA receptors in the basal ganglia of girls with Rett syndrome. Experimental Neurology, 156, 345–352.CrossRefPubMed

Blusztajn, J. K., & Wurtman, R. J. (1983). Choline and cholinergic neurons. Science, 221, 614–620.CrossRefPubMed

Casanova, M. F., Buxhoeveden, D., Switala, A., & Roy, E. (2003). Rett syndrome as a minicolumnopathy. Clinical Neuropathology, 22, 163–168.PubMed

Chahrour, M., & Zoghbi, H. Y. (2007). The story of Rett syndrome: From clinic to neurobiology. Neuron, 56, 422–437.CrossRefPubMed

Chao, H., Zoghbi, H. Y., & Rosenmund, C. (2007). MeCP2 controls excitatory synaptic strength by regulating glutamatergic synapse number. Neuron, 56, 1–8.CrossRef

Christian, K., Song, H., & Ming, G. (2012). Application of reprogrammed patient cells to investigate the etiology of neurological and psychiatric disorders. Frontiers in Biology, 7, 179–188.CrossRef

Dimos, J. T., Rodolfa, K. T., Niakan, K. K., Weisenthal, L. M., Mitsumoto, H., Chung, W., et al. (2008). Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science, 321, 1218–1221.CrossRefPubMed

Ebert, A. D., Yu, J., Rose, F. F, Jr., Mattis, V. B., Lorson, C. L., Thomson, J. A., & Svendsen, C. N. (2009). Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature, 457, 277–280.CrossRefPubMed

Fischer, M. C., Zeisel, S. H., Mar, M. H., & Sadler, T. W. (2001). Inhibitors of choline uptake and metabolism cause developmental abnormalities in neurulating mouse embryos. Teratology, 64, 114–122.CrossRef

Fisher, S. K., Heacock, A. M., Keep, R. F., & Foster, D. J. (2010). Receptor regulation of osmolyte homeostasis in neural cells. Journal of Physiology, 588, 3355–3364.CrossRefPubMedPubMedCentral

Fukuda, T., Itoh, M., Ichikawa, T., Washiyama, K., & Goto, Y. (2005). Delayed maturation of neuronal architecture and synaptogenesis in cerebral cortex of Mecp2-deficient mice. Journal of Neuropathology and Experimental Neurology, 64, 537–544.CrossRefPubMed

Gallazzini, M., Ferraris, J. D., Kunin, M., Morris, R. G., & Burg, M. B. (2006). Neuropathy target esterase catalyzes osmoprotective renal synthesis of glycerophosphocholine in response to high NaCl. Proceedings of the National Academy of Sciences, USA, 103, 15260–15265.CrossRef

Guy, J., Gan, J., Selfridge, J., Cobb, S., & Bird, A. (2007). Reversal of neurological defects in a mouse model of Rett syndrome. Science, 315, 1143–1147.CrossRefPubMed

Hagberg, B., Aicardi, J., Dias, K., & Ramos, O. (1983). A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett’s syndrome: Report of 35 cases. Annals of Neurology, 14, 471–479.CrossRefPubMed

Henneberry, A. L., Lagace, T. A., Ridgway, N. D., & McMaster, C. R. (2001). Phosphatidylcholine synthesis influences the diacylglycerol homeostasis required for Sec14p-dependent Golgi function and cell growth. Molecular Biology of the Cell, 12, 511–520.CrossRefPubMedPubMedCentral

Hilfiker, S., Pieribone, V. A., Czernik, A. J., Kao, H. T., Augustine, G. J., & Greengard, P. (1999). Synapsins as regulators of neurotransmitter release. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 354(1381), 269–279.CrossRefPubMedPubMedCentral

Huppke, P., Laccone, F., Kramer, N., Engel, W., & Hanefeld, F. (2000). Rett syndrome: Analysis of MECP2 and clinical characterization of 31 patients. Human Molecular Genetics, 9, 1369–1375.CrossRefPubMed

Johnston, M. V., Blue, M. E., & Naidu, S. (2005). Rett syndrome and neuronal development. Journal of Child Neurology, 20, 759–763.CrossRefPubMed

Kearns, B. G., McGee, T. P., Mayinger, P., Gedvilaite, A., Phillips, S. E., Kagiwada, S., & Bankaitis, V. A. (1997). Essential role for diacylglycerol in protein transport from the yeast Golgi complex. Nature (London), 387, 101–105.CrossRef

Kerr, A. M., & Stephenson, J. B. (1985). Rett’s syndrome in the west of Scotland. British Medical Journal (Clinical Research Ed.), 291, 579–582.CrossRef

Kitt, C. A., & Wilcox, B. J. (1995). Preliminary evidence for neurodegenerative changes in the substantia nigra of Rett syndrome. Neuropediatrics, 26, 114–118.CrossRefPubMed

Lee, S. S., Wan, M., & Francke, U. (2001). Spectrum of MECP2 mutations in Rett syndrome. Brain Development, 23(Suppl 1), S138–S143.PubMed

Ma, D., Yoon, S.-I., Yang, C.-H., Marcy, G., Zhao, N., Leong, W.-Y., et al. (2015). Rescue of methyl-CpG binding protein 2 dysfunction-induced defects in newborn neurons by pentobarbital. Neurotherapeutics, 12(2), 477–490.CrossRefPubMedPubMedCentral

Marchetto, M. C. N., Carromeu, C., Acab, A., Yu, D., Yeo, G. W., Mu, Y., et al. (2010a). A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell, 143, 527–539.CrossRefPubMedPubMedCentral

Marchetto, M. C., Winner, B., & Gage, F. H. (2010b). Pluripotent stem cells in neurodegenerative and neurodevelopmental diseases. Human Molecular Genetics, 19(R1), R71–R76.CrossRefPubMedPubMedCentral

McMaster, C. R. (2001). Lipid metabolism and vesicle trafficking: More than just greasing the transport machinery. Biochemistry and Cell Biology, 79, 681–692.CrossRefPubMed

Medrihan, L., Tantalaki, E., Aramuni, G., Sargsyan, V., Dudanova, I., Missler, M., & Zhang, W. (2008). Early defects of GABAergic synapses in the brainstem of a MeCP2 mouse model of Rett syndrome. Journal of Neurophysiology, 99(1), 112–121.CrossRefPubMed

Muotri, A. R. (2008). Modeling epilepsy with pluripotent human cells. Epilepsy & Behavior, 14((Suppl.)), 81–85.

Nag, N., Mellott, T. J., & Berger-Sweeney, J. E. (2008). Effects of postnatal dietary choline supplementation on motor regional brain volume and growth factor expression in a mouse model of Rett syndrome. Brain Research, 1237, 101–109.CrossRefPubMed

Oda, Y. (1999). Choline acetyltransferase: The structure, distribution and pathologic changes in the central nervous system. Pathology International, 49(11), 921–937.CrossRefPubMed

Siddique, M. M., Li, Y., Wang, L., Ching, J., Mal, M., Ilkayeva, O., et al. (2013). Ablation of dihydroceramide desaturase 1, a therapeutic target for the treatment of metabolic diseases, simultaneously stimulates anabolic and catabolic signaling. Molecular and Cellular Biology, 33(11), 2353–2369.CrossRefPubMedPubMedCentral

Sinha, R. A., Farah, B. L., Singh, B. K., Siddique, M. M., Li, Y., Wu, Y., et al. (2014). Caffeine stimulates hepatic lipid metabolism by the autophagy-lysosomal pathway in mice. Hepatology, 59(4), 1366–1380.CrossRefPubMed

Soldner, F., Hockemeyer, D., Beard, C., Gao, Q., Bell, G. W., Cook, E. G., et al. (2009). Parkinson’s disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell, 136, 964–977.CrossRefPubMedPubMedCentral

Su, C. T. E., Yoon, S. I., Marcy, G., Chin, E. W. M., Augustine, G. J., & Goh, E. L. K. (2015). An optogenetic approach for assessing formation of neuronal connections in a co-culture system. Journal of Visualized Experiments, 96, e52408.PubMed

Verpelli, C., Carlessi, L., Bechi, G., Poli, E. F., Orellana, D., Heise, C., et al. (2013). Comparative neuronal differentiation of self-renewing neural progenitor cell lines obtained from human induced pluripotent stem cells. Frontiers in Cellular Neuroscience, 7, 175.CrossRefPubMedPubMedCentral

Viola, A., Saywell, V., Villard, L., Cozzone, P. J., & Lutz, N. W. (2007). Metabolic fingerprints of altered brain growth, osmoregulation and neurotransmission in a Rett syndrome model. PLoS One, 2(1), e157.CrossRefPubMedPubMedCentral

Wan, M., Lee, S. S., Zhang, X., Houwink-Manville, I., Song, H. R., Amir, R. E., et al. (1999). Rett syndrome and beyond: Recurrent spontaneous and familial MECP2 mutations at CpG hotspots. American Journal of Human Genetics, 65, 1520–1529.CrossRefPubMedPubMedCentral

Weick, J. P., Liu, Y., & Zhang, S.-C. (2011). Human embryonic stem cell-derived neurons adopt and regulate the activity of an established neural network. Proceedings of National Academy of Sciences, 108(50), 20189–20194.CrossRef

Wenk, G. L. (1995). Alterations in dopaminergic function in Rett syndrome. Neuropediatrics, 26, 123–125.CrossRefPubMed

Wenk, G. L., & Hauss-Wegrzyniak, B. (1999). Altered cholinergic function in the basal forebrain of girls with Rett syndrome. Neuropediatrics, 30, 125–129.CrossRefPubMed

Wenk, G. L., Naidu, S., Casanova, M. F., Kitt, C. A., & Moser, H. (1991). Altered neurochemical markers in Rett’s syndrome. Neurology, 41, 1753–1756.CrossRefPubMed

Woolf, N. J. (1991). Cholinergic systems in mammalian brain and spinal cord. Progress in Neurobiology, 37, 475–524.CrossRefPubMed

Zhang, X. H., Zhao, C., Seleznev, K., Song, K., Manfredi, J. J., et al. (2006). Disruption of G1-phase phospholipid turnover by inhibition of Ca2+ -independent phospholipase A2 induces a p53-dependent cell-cycle arrest in G1 phase. Journal of Cell Science, 119, 1005–1015.CrossRefPubMedPubMedCentral

Titel: Choline Ameliorates Disease Phenotypes in Human iPSC Models of Rett Syndrome
verfasst von: Eunice W. M. Chin
Guillaume Marcy
Su-In Yoon
Dongliang Ma
Francisco J. Rosales
George J. Augustine
Eyleen L. K. Goh
Publikationsdatum: 05.07.2016
Verlag: Springer US
Erschienen in: NeuroMolecular Medicine / Ausgabe 3/2016
Print ISSN: 1535-1084
Elektronische ISSN: 1559-1174
DOI: https://doi.org/10.1007/s12017-016-8421-y

Leitlinien kompakt für die Neurologie

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Neurologie

Hirnblutung unter DOAK und VKA ähnlich bedrohlich

17.05.2024 Direkte orale Antikoagulanzien Nachrichten

Kommt es zu einer nichttraumatischen Hirnblutung, spielt es keine große Rolle, ob die Betroffenen zuvor direkt wirksame orale Antikoagulanzien oder Marcumar bekommen haben: Die Prognose ist ähnlich schlecht.

Thrombektomie auch bei großen Infarkten von Vorteil

16.05.2024 Ischämischer Schlaganfall Nachrichten

Auch ein sehr ausgedehnter ischämischer Schlaganfall scheint an sich kein Grund zu sein, von einer mechanischen Thrombektomie abzusehen. Dafür spricht die LASTE-Studie, an der Patienten und Patientinnen mit einem ASPECTS von maximal 5 beteiligt waren.

Schwindelursache: Massagepistole lässt Otholiten tanzen

14.05.2024 Benigner Lagerungsschwindel Nachrichten

Wenn jüngere Menschen über ständig rezidivierenden Lagerungsschwindel klagen, könnte eine Massagepistole der Auslöser sein. In JAMA Otolaryngology warnt ein Team vor der Anwendung hochpotenter Geräte im Bereich des Nackens.

Schützt Olivenöl vor dem Tod durch Demenz?

10.05.2024 Morbus Alzheimer Nachrichten

Konsumieren Menschen täglich 7 Gramm Olivenöl, ist ihr Risiko, an einer Demenz zu sterben, um mehr als ein Viertel reduziert – und dies weitgehend unabhängig von ihrer sonstigen Ernährung. Dafür sprechen Auswertungen zweier großer US-Studien.

Update Neurologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Die Highlights vom Kongress des American College of Cardiology 2024

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 3/2016

Effects of Long-Term Rice Bran Extract Supplementation on Survival, Cognition and Brain Mitochondrial Function in Aged NMRI Mice

Preserving Brain Function in Aging: The Anti-glycative Potential of Berry Fruit

Recommendations for Development of Botanical Polyphenols as “Natural Drugs” for Promotion of Resilience Against Stress-Induced Depression and Cognitive Impairment

Protective Effects of AGE and Its Components on Neuroinflammation and Neurodegeneration

Nutraceuticals in Neurodegeneration and Aging