Proteomic, genomic and translational approaches identify CRMP1 for a role in schizophrenia and its underlying traits

Verian Bader, Liisa Tomppo, Svenja V. Trossbach, Nicholas J. Bradshaw, Ingrid Prikulis, S. Rutger Leliveld, Chi Ying Lin, Koko Ishizuka, Akira Sawa, Adriana Ramos, Isaac Rosa, Ångel García, Jesús R. Requena, Maria Hipolito, Narayan Rai, Evaristus Nwulia, Uwe Henning, Stefano Ferrea, Christian Luckhaus, Jesper EkelundJuha Veijola, Marjo Riitta Järvelin, William Hennah, Carsten Korth

Research output: Contribution to journalArticlepeer-review

48 Scopus citations


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.

Original languageEnglish (US)
Article numberdds273
Pages (from-to)4406-4418
Number of pages13
JournalHuman molecular genetics
Issue number20
StatePublished - Oct 2012

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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