Proteomic, genomic and translational approaches identify CRMP1 for a role in schizophrenia and its underlying traits
Proteomic, genomic and translational approaches identify CRMP1 for a role in schizophrenia and its underlying traits
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DOI：
10.1093/hmg/dds273
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发表时间：
2012-10-15
影响因子：
3.5
通讯作者：
Korth, Carsten
中科院分区：
文献类型：
--
作者：
Bader, Verian;Tomppo, Liisa;Korth, Carsten
精神分裂症是一种异质生物起源的慢性疾病。我们假设，与慢性进行性脑部疾病类似，神经元的持续功能紊乱将导致精神分裂症患者大脑中的蛋白质稳态紊乱，导致特定错误折叠、不溶性蛋白质的丰度增加。鉴定此类蛋白质将有助于阐明这些破坏性条件下的分子过程。因此，我们针对精神分裂症患者死后大脑的汇集不溶性蛋白质组产生了抗体，以便识别独特的疾病特异性表位。我们成功地鉴定了这样一个表位，该表位存在于生化纯化的不溶性脑组分中的崩溃素反应介导蛋白 1 (CRMP1) 上。对芬兰大型人群 (n 4651) 中的 CRMP1 基因进行的遗传关联分析证实了身体和社交快感缺失与 CRMP1 基因座以 DISC1（精神分裂症中断 1）依赖性方式的关联。身体和社交快感缺乏是可遗传的特征，表现为精神分裂症和严重抑郁症的慢性阴性症状，从而构成精神疾病的严重脆弱因素。引人注目的是，源自精神分裂症患者的淋巴母细胞系通过显示 CRMP1 表达增加来反映异常的 CRMP1 免疫反应性，表明其作为血液诊断标记物的潜在作用。 CRMP1 是一种新的精神分裂症特征候选蛋白，位于 reelin 和 DISC1 通路的交叉点，与 DISC1 直接和功能性相互作用。我们展示了跨学科方法的影响，其中在遗传关联研究的支持下，对死后大脑中疾病相关表位的识别迅速转化为潜在的基于血液的诊断标记物。
Schizophrenia is a chronic illness of heterogenous biological origin. We hypothesized that, similar to chronic progressive brain conditions, persistent functional disturbances of neurons would result in disturbed proteostasis in the brains of schizophrenia patients, leading to increased abundance of specific misfolded, insoluble proteins. Identification of such proteins would facilitate the elucidation of molecular processes underlying these devastating conditions. We therefore generated antibodies against pooled insoluble proteome of post-mortem brains from schizophrenia patients in order to identify unique, disease-specific epitopes. We successfully identified such an epitope to be present on collapsin-response mediator protein 1 (CRMP1) in biochemically purified, insoluble brain fractions. A genetic association analysis for the CRMP1 gene in a large Finnish population cohort (n 4651) corroborated the association of physical and social anhedonia with the CRMP1 locus in a DISC1 (Disrupted-in-schizophrenia 1)-dependent manner. Physical and social anhedonia are heritable traits, present as chronic, negative symptoms of schizophrenia and severe major depression, thus constituting serious vulnerability factors for mental disease. Strikingly, lymphoblastoid cell lines derived from schizophrenia patients mirrored aberrant CRMP1 immunoreactivity by showing an increase of CRMP1 expression, suggesting its potential role as a blood-based diagnostic marker. CRMP1 is a novel candidate protein for schizophrenia traits at the intersection of the reelin and DISC1 pathways that directly and functionally interacts with DISC1. We demonstrate the impact of an interdisciplinary approach where the identification of a disease-associated epitope in post-mortem brains, powered by a genetic association study, is rapidly translated into a potential blood-based diagnostic marker.