Pagan Cécile, Benabou Marion, Leblond Claire, Cliquet Freddy, Mathieu Alexandre, Lemière Nathalie, Goubran-Botros Hany, Delorme Richard, Leboyer Marion, Callebert Jacques, Bourgeron Thomas, Launay Jean-Marie
Service de Biochimie et Biologie Moléculaire, INSERM U942, Hôpital Lariboisière, AP-HP, Paris, France.
Fondation Fondamental, Créteil, France.
Transl Psychiatry. 2021 Jan 7;11(1):23. doi: 10.1038/s41398-020-01125-5.
Hyperserotonemia is the most replicated biochemical abnormality associated with autism spectrum disorders (ASD). However, previous studies of serotonin synthesis, catabolism, and transport have not elucidated the mechanisms underlying this hyperserotonemia. Here we investigated serotonin sulfation by phenol sulfotransferases (PST) in blood samples from 97 individuals with ASD and their first-degree relatives (138 parents and 56 siblings), compared with 106 controls. We report a deficient activity of both PST isoforms (M and P) in platelets from individuals with ASD (35% and 78% of patients, respectively), confirmed in autoptic tissues (9 pineal gland samples from individuals with ASD-an important source of serotonin). Platelet PST-M deficiency was strongly associated with hyperserotonemia in individuals with ASD. We then explore genetic or pharmacologic modulation of PST activities in mice: variations of PST activities were associated with marked variations of blood serotonin, demonstrating the influence of the sulfation pathway on serotonemia. We also conducted in 1645 individuals an extensive study of SULT1A genes, encoding PST and mapping at highly polymorphic 16p11.2 locus, which did not reveal an association between copy number or single nucleotide variations and PST activity, blood serotonin or the risk of ASD. In contrast, our broader assessment of sulfation metabolism in ASD showed impairments of other sulfation-related markers, including inorganic sulfate, heparan-sulfate, and heparin sulfate-sulfotransferase. Our study proposes for the first time a compelling mechanism for hyperserotonemia, in a context of global impairment of sulfation metabolism in ASD.
高血清素血症是与自闭症谱系障碍（ASD）相关的最具重复性的生化异常。然而，先前关于血清素合成、分解代谢和转运的研究尚未阐明这种高血清素血症的潜在机制。在此，我们研究了97名患有ASD的个体及其一级亲属（138名父母和56名兄弟姐妹）的血液样本中苯酚硫酸转移酶（PST）介导的血清素硫酸化情况，并与106名对照进行了比较。我们报告了患有ASD的个体血小板中两种PST同工型（M和P）的活性不足（分别为35%和78%的患者），这在尸检组织中得到了证实（9份来自患有ASD个体的松果体样本——血清素的一个重要来源）。血小板PST-M缺乏与患有ASD的个体的高血清素血症密切相关。然后，我们探索了小鼠中PST活性的遗传或药物调节：PST活性的变化与血液血清素的显著变化相关，这表明硫酸化途径对血清素血症的影响。我们还对1645名个体进行了一项关于SULT1A基因的广泛研究，该基因编码PST并定位于高度多态的16p11.2位点，研究未发现拷贝数或单核苷酸变异与PST活性、血液血清素或ASD风险之间存在关联。相比之下，我们对ASD中硫酸化代谢的更广泛评估显示其他硫酸化相关标志物存在损伤，包括无机硫酸盐、硫酸乙酰肝素和硫酸乙酰肝素硫酸转移酶。我们的研究首次在ASD硫酸化代谢全面受损的背景下，提出了一个令人信服的高血清素血症机制。
