Nagaoka Atsuko, Kunii Yasuto, Hino Mizuki, Izumi Ryuta, Nagashima Chisato, Takeshima Akari, Sainouchi Makoto, Nawa Hiroyuki, Kakita Akiyoshi, Yabe Hirooki
Department of Neuropsychiatry, School of Medicine, Fukushima Medical University, 960-1295, Fukushima, Japan.
Department of Neuropsychiatry, School of Medicine, Fukushima Medical University, 960-1295, Fukushima, Japan; Department of Psychiatry, Aizu Medical Center, Fukushima Medical University, 969-3492, Fukushima, Japan.
J Psychiatr Res. 2020 Apr;123:119-127. doi: 10.1016/j.jpsychires.2020.02.001. Epub 2020 Feb 6.
The molecular mechanisms underlying schizophrenia remain largely unclear, and we recently identified multiple proteins significantly altered in the postmortem prefrontal cortex (PFC) of schizophrenia patients amongst which aldehyde dehydrogenase 4 family member A1 (ALDH4A1) was especially elevated. In this study, we aimed to investigate the expression of ALDH4A1 in the PFC and superior temporal gyrus (STG) and to elucidate functional correlations between schizophrenia risk alleles and molecular expression profiles in the postmortem brains of patients with schizophrenia.
The levels of ALDH4A1 protein expression in the PFC and STG in postmortem brains from 24 patients with schizophrenia, 8 patients with bipolar disorder, and 32 controls were assessed using enzyme-linked immunosorbent assay. Moreover, we explored the associations between ALDH4A1 expression and genetic variants in enzymes associated with proline metabolism, including ALDH4A1 (schizophrenia [n = 22], bipolar disorder [n = 6], controls [n = 11]).
ALDH4A1 levels were significantly elevated in both the PFC and STG in patients with schizophrenia and tended to elevate in patients with bipolar disorder. Furthermore, ALDH4A1 expression levels in the PFC were significantly associated with the following three single-nucleotide polymorphisms: rs10882639, rs33823, rs153508. We also found partial coexpression of ALDH4A1 in mitochondria in a subset of putative astrocytes of postmortem brain.
Our study population was relatively small, particularly for a genetic study.
These findings indicate that altered expression of ALDH4A1 may reflect the potential molecular mechanisms underlying the pathogenesis of schizophrenia and bipolar disorder, and may aid in the development of novel drug therapies.
精神分裂症的分子机制在很大程度上仍不清楚，我们最近在精神分裂症患者的死后前额叶皮质（PFC）中鉴定出多种显著改变的蛋白质，其中醛脱氢酶4家族成员A1（ALDH4A1）尤其升高。在本研究中，我们旨在研究ALDH4A1在PFC和颞上回（STG）中的表达，并阐明精神分裂症风险等位基因与精神分裂症患者死后大脑分子表达谱之间的功能相关性。
使用酶联免疫吸附测定法评估24例精神分裂症患者、8例双相情感障碍患者和32例对照者死后大脑中PFC和STG中ALDH4A1蛋白表达水平。此外，我们探讨了ALDH4A1表达与脯氨酸代谢相关酶的基因变异之间的关联，这些酶包括ALDH4A1（精神分裂症[n = 22]、双相情感障碍[n = 6]、对照[n = 11]）。
精神分裂症患者的PFC和STG中ALDH4A1水平均显著升高，双相情感障碍患者有升高趋势。此外，PFC中ALDH4A1表达水平与以下三个单核苷酸多态性显著相关：rs10882639、rs33823、rs153508。我们还在死后大脑一部分假定的星形胶质细胞的线粒体中发现了ALDH4A1的部分共表达。
我们的研究人群相对较小，特别是对于基因研究而言。
这些发现表明，ALDH4A1表达改变可能反映了精神分裂症和双相情感障碍发病机制的潜在分子机制，并可能有助于开发新的药物疗法。
