Evidence for Altered Metabolism of Sphingosine-1-Phosphate in the Corpus Callosum of Patients with Schizophrenia.
Evidence for Altered Metabolism of Sphingosine-1-Phosphate in the Corpus Callosum of Patients with Schizophrenia.
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精神分裂症患者胼胝体鞘鞘醇-1-磷酸代谢改变的证据。
DOI：
10.1093/schbul/sbaa052
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发表时间：
2020-09-21
影响因子：
6.6
通讯作者：
Yoshikawa T
中科院分区：
文献类型：
--
作者：
Esaki K;Balan S;Iwayama Y;Shimamoto-Mitsuyama C;Hirabayashi Y;Dean B;Yoshikawa T
髓磷脂和白质完整性的紊乱，以及脂质代谢的失调，可能与精神分裂症的病理生理有关。考虑到鞘脂在神经发育中的关键作用，特别是在少突胶质细胞分化和髓鞘形成中，我们研究了鞘脂动力学在精神分裂症病理生理中的作用。我们对来自精神分裂症患者和对照组的死后脑样本的皮质区和胼胝体的鞘脂进行了靶向质谱分析。与对照组相比，我们观察到鞘氨醇-1-磷酸（S1P）水平较低，特别是在精神分裂症患者的胼胝体中，但在重度抑郁症或双相情感障碍患者中没有。患者数据和动物研究表明，服用抗精神病药物不会导致S1P水平降低。我们还发现，精神分裂症患者胼胝体中S1P水平的降低可能源于S1P降解酶基因的上调；S1P受体基因的高表达提示了S1P水平降低的潜在补偿机制。在精神分裂症患者的样本中，鞘氨醇和神经酰胺与S1P的比例也高于对照组，S1P可以诱导细胞凋亡和细胞周期阻滞。这些结果表明，S1P代谢的改变可能是少突胶质细胞分化和髓磷脂形成缺陷的基础，导致精神分裂症中白质的结构和分子异常。我们的发现可能会为一种新的治疗策略铺平道路。
The disturbed integrity of myelin and white matter, along with dysregulation of the lipid metabolism, may be involved in schizophrenia pathophysiology. Considering the crucial role of sphingolipids in neurodevelopment, particularly in oligodendrocyte differentiation and myelination, we examined the role of sphingolipid dynamics in the pathophysiology of schizophrenia. We performed targeted mass spectrometry-based analysis of sphingolipids from the cortical area and corpus callosum of postmortem brain samples from patients with schizophrenia and controls. We observed lower sphingosine-1-phosphate (S1P) levels, specifically in the corpus callosum of patients with schizophrenia, but not in major depressive disorder or bipolar disorder, when compared with the controls. Patient data and animal studies showed that antipsychotic intake did not contribute to the lowered S1P levels. We also found that lowered S1P levels in the corpus callosum of patients with schizophrenia may stem from the upregulation of genes for S1P-degrading enzymes; higher expression of genes for S1P receptors suggested a potential compensatory mechanism for the lowered S1P levels. A higher ratio of the sum of sphingosine and ceramide to S1P, which can induce apoptosis and cell-cycle arrest, was also observed in the samples of patients with schizophrenia than in controls. These results suggest that an altered S1P metabolism may underlie the deficits in oligodendrocyte differentiation and myelin formation, leading to the structural and molecular abnormalities of white matter reported in schizophrenia. Our findings may pave the way toward a novel therapeutic strategy.
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DOI：
10.1126/science.1176709
发表时间：
2009-09-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hait NC;Allegood J;Maceyka M;Strub GM;Harikumar KB;Singh SK;Luo C;Marmorstein R;Kordula T;Milstien S;Spiegel S
通讯作者：
Spiegel S
影响因子：
11
作者：
Kelly S;Jahanshad N;Zalesky A;Kochunov P;Agartz I;Alloza C;Andreassen OA;Arango C;Banaj N;Bouix S;Bousman CA;Brouwer RM;Bruggemann J;Bustillo J;Cahn W;Calhoun V;Cannon D;Carr V;Catts S;Chen J;Chen JX;Chen X;Chiapponi C;Cho KK;Ciullo V;Corvin AS;Crespo-Facorro B;Cropley V;De Rossi P;Diaz-Caneja CM;Dickie EW;Ehrlich S;Fan FM;Faskowitz J;Fatouros-Bergman H;Flyckt L;Ford JM;Fouche JP;Fukunaga M;Gill M;Glahn DC;Gollub R;Goudzwaard ED;Guo H;Gur RE;Gur RC;Gurholt TP;Hashimoto R;Hatton SN;Henskens FA;Hibar DP;Hickie IB;Hong LE;Horacek J;Howells FM;Hulshoff Pol HE;Hyde CL;Isaev D;Jablensky A;Jansen PR;Janssen J;Jönsson EG;Jung LA;Kahn RS;Kikinis Z;Liu K;Klauser P;Knöchel C;Kubicki M;Lagopoulos J;Langen C;Lawrie S;Lenroot RK;Lim KO;Lopez-Jaramillo C;Lyall A;Magnotta V;Mandl RCW;Mathalon DH;McCarley RW;McCarthy-Jones S;McDonald C;McEwen S;McIntosh A;Melicher T;Mesholam-Gately RI;Michie PT;Mowry B;Mueller BA;Newell DT;O'Donnell P;Oertel-Knöchel V;Oestreich L;Paciga SA;Pantelis C;Pasternak O;Pearlson G;Pellicano GR;Pereira A;Pineda Zapata J;Piras F;Potkin SG;Preda A;Rasser PE;Roalf DR;Roiz R;Roos A;Rotenberg D;Satterthwaite TD;Savadjiev P;Schall U;Scott RJ;Seal ML;Seidman LJ;Shannon Weickert C;Whelan CD;Shenton ME;Kwon JS;Spalletta G;Spaniel F;Sprooten E;Stäblein M;Stein DJ;Sundram S;Tan Y;Tan S;Tang S;Temmingh HS;Westlye LT;Tønnesen S;Tordesillas-Gutierrez D;Doan NT;Vaidya J;van Haren NEM;Vargas CD;Vecchio D;Velakoulis D;Voineskos A;Voyvodic JQ;Wang Z;Wan P;Wei D;Weickert TW;Whalley H;White T;Whitford TJ;Wojcik JD;Xiang H;Xie Z;Yamamori H;Yang F;Yao N;Zhang G;Zhao J;van Erp TGM;Turner J;Thompson PM;Donohoe G
通讯作者：
Donohoe G
DOI：
10.1016/0169-328x(94)00219-5
发表时间：
1995-02-01
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
KINGSBURY, AE;FOSTER, OJF;MARSDEN, CD
通讯作者：
MARSDEN, CD
影响因子：
4.4
作者：
Bator, Ewelina;Latusz, Joachim;Mackowiak, Marzena
通讯作者：
Mackowiak, Marzena
影响因子：
11
作者：
Greene C;Kealy J;Humphries MM;Gong Y;Hou J;Hudson N;Cassidy LM;Martiniano R;Shashi V;Hooper SR;Grant GA;Kenna PF;Norris K;Callaghan CK;Islam MD;O'Mara SM;Najda Z;Campbell SG;Pachter JS;Thomas J;Williams NM;Humphries P;Murphy KC;Campbell M
通讯作者：
Campbell M