Transcriptome analysis of human induced excitatory neurons supports a strong effect of clozapine on cholesterol biosynthesis.
作者： Joel S. Bader , Anh Thu N. Lam , Debamitra Das , Xi Peng , Dimitrios Avramopoulos
DOI: 10.1016/J.SCHRES.2020.12.041
关键词: Function (biology) 、 Excitatory postsynaptic potential 、 Dopamine 、 Mechanism (biology) 、 Induced pluripotent stem cell 、 Neuroscience 、 Clozapine 、 Transcriptome 、 Schizophrenia 、 Biology
摘要: Abstract Antipsychotics are known to modulate dopamine and other neurotransmitters which is often thought be the mechanism underlying their therapeutic effects. Nevertheless, less studied consequences of antipsychotics on neuronal function may contribute efficacy. Revealing complete picture behind action paramount importance for precision medicine accurate drug selection. Progress in cell engineering allows generation induced pluripotent stem cells (iPSCs) differentiation a variety types, providing new tools study antipsychotics. Here we use excitatory cortical neurons derived from iPSCs explore response levels Clozapine as measured by transcriptomic output, proxy homeostasis. To our surprise, but agreement with results many investigators studying glial-like cells, had very strong effect cholesterol metabolism. More than quarter (12) all annotated genes (46) genome were significantly changed at FDR
elsevier.com
sci-hub.st 参考文章(15)
Gerd Schmitz, Evelyn Orsó, Intracellular Cholesterol and Phospholipid Trafficking: Comparable Mechanisms in Macrophages and Neuronal Cells Neurochemical Research. ,vol. 26, pp. 1045- 1068 ,(2001) , 10.1023/A:1012357106398
Soo-Han BAE, Young-Ki PAIK, Cholesterol biosynthesis from lanosterol: development of a novel assay method and characterization of rat liver microsomal lanosterol delta 24-reductase. Biochemical Journal. ,vol. 326, pp. 609- 616 ,(1997) , 10.1042/BJ3260609
Juan Zhang, Qiang Liu, Cholesterol metabolism and homeostasis in the brain. Protein & Cell. ,vol. 6, pp. 254- 264 ,(2015) , 10.1007/S13238-014-0131-3
J Fernø, M B Raeder, A O Vik-Mo, S Skrede, M Glambek, K-J Tronstad, H Breilid, R Løvlie, R K Berge, C Stansberg, V M Steen, Antipsychotic drugs activate SREBP-regulated expression of lipid biosynthetic genes in cultured human glioma cells: a novel mechanism of action? Pharmacogenomics Journal. ,vol. 5, pp. 298- 304 ,(2005) , 10.1038/SJ.TPJ.6500323
Cesare R. Sirtori, The pharmacology of statins Pharmacological Research. ,vol. 88, pp. 3- 11 ,(2014) , 10.1016/J.PHRS.2014.03.002
Yingsha Zhang, ChangHui Pak, Yan Han, Henrik Ahlenius, Zhenjie Zhang, Soham Chanda, Samuele Marro, Christopher Patzke, Claudio Acuna, Jason Covy, Wei Xu, Nan Yang, Tamas Danko, Lu Chen, Marius Wernig, Thomas C. Südhof, Rapid Single-Step Induction of Functional Neurons from Human Pluripotent Stem Cells Neuron. ,vol. 78, pp. 785- 798 ,(2013) , 10.1016/J.NEURON.2013.05.029
Frank W Pfrieger, Role of cholesterol in synapse formation and function. Biochimica et Biophysica Acta. ,vol. 1610, pp. 271- 280 ,(2003) , 10.1016/S0005-2736(03)00024-5
Mihael H. Polymeropoulos, Louis Licamele, Simona Volpi, Kendra Mack, Shruti N. Mitkus, Eugene D. Carstea, Lise Getoor, Andrew Thompson, Christian Lavedan, Common effect of antipsychotics on the biosynthesis and regulation of fatty acids and cholesterol supports a key role of lipid homeostasis in schizophrenia Schizophrenia Research. ,vol. 108, pp. 134- 142 ,(2009) , 10.1016/J.SCHRES.2008.11.025
Audun O Vik-Mo, Johan Fernø, Silje Skrede, Vidar M Steen, Psychotropic drugs up-regulate the expression of cholesterol transport proteins including ApoE in cultured human CNS- and liver cells BMC Pharmacology. ,vol. 9, pp. 10- 10 ,(2009) , 10.1186/1471-2210-9-10
Elaine Tierney, Ngozi A. Nwokoro, Forbes D. Porter, Lisa S. Freund, Jaswinder K. Ghuman, Richard I. Kelley, Behavior phenotype in the RSH/Smith-Lemli-Opitz syndrome. American Journal of Medical Genetics. ,vol. 98, pp. 191- 200 ,(2001) , 10.1002/1096-8628(20010115)98:2<191::AID-AJMG1030>3.0.CO;2-M