Enhanced carbonyl stress induces irreversible multimerization of CRMP2 in schizophrenia pathogenesis
Enhanced carbonyl stress induces irreversible multimerization of CRMP2 in schizophrenia pathogenesis
复制标题
DOI：
10.26508/lsa.201900478
复制
发表时间：
2019-10-01
影响因子：
4.4
通讯作者：
Hirokawa, Nobutaka
中科院分区：
文献类型：
--
作者：
Toyoshima, Manabu;Jiang, Xuguang;Hirokawa, Nobutaka
加强的羰基应激是精神分裂症的一个子集，但其因果影响仍然难以捉摸。在此，我们阐明了羰基应激对iPS细胞的影响的分子机制，其中编码锌金属酶乙二醛酶1(GLO1)的基因被破坏，GLO1是清除羰基应激的关键酶。IPS细胞表现出明显的细胞和发育缺陷，以及崩溃反应介体蛋白2(CRMP2)的超甲基化。结构和生化分析表明，在CRMP2的功能基序中有一系列多个羰化位点，特别是D-钩(用于二聚)和T-位(用于四聚)，它们对CRMP2四聚体的活性至关重要。有趣的是，碳化的CRMP2通过不可逆的交联堆积在多聚体构象中，导致其独特的微管捆绑功能丧失。因此，本研究揭示了由遗传异常引起的增强的羰基应激通过形成不可逆的功能障碍的多聚体来导致神经发育缺陷。
Enhanced carbonyl stress underlies a subset of schizophrenia, but its causal effects remain elusive. Here, we elucidated the molecular mechanism underlying the effects of carbonyl stress in iPS cells in which the gene encoding zinc metalloenzyme glyoxalase 1 (GLO1), a crucial enzyme for the clearance of carbonyl stress, was disrupted. The iPS cells exhibited significant cellular and developmental deficits, and hyper-carbonylation of collapsing response mediator protein 2 (CRMP2). Structural and biochemical analyses revealed an array of multiple carbonylation sites in the functional motifs of CRMP2, particularly D-hook (for dimerization) and T-site (for tetramerization), which are critical for the activity of the CRMP2 tetramer. Interestingly, carbonylated CRMP2 was stacked in the multimer conformation by irreversible cross-linking, resulting in loss of its unique function to bundle microtubules. Thus, the present study revealed that the enhanced carbonyl stress stemmed from the genetic aberrations results in neurodevelopmental deficits through the formation of irreversible dysfunctional multimer of carbonylated CRMP2.