Journal Article

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, Ángel García, Jesús R. Requena, Maria Hipolito, Narayan Rai, Evaristus Nwulia, Uwe Henning, Stefano Ferrea, Christian Luckhaus, Jesper Ekelund, Juha Veijola, Marjo-Riitta Järvelin, William Hennah and Carsten Korth

in Human Molecular Genetics

Volume 21, issue 20, pages 4406-4418
Published in print October 2012 | ISSN: 0964-6906
Published online July 2012 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/dds273
Proteomic, genomic and translational approaches identify CRMP1 for a role in schizophrenia and its underlying traits

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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.

Journal Article.  7324 words.  Illustrated.

Subjects: Genetics and Genomics

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