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

ABSTRACT: 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.

SUBMITTER: Bader V

PROVIDER: S-EPMC3529585 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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

Bader Verian V Tomppo Liisa L Trossbach Svenja V SV Bradshaw Nicholas J NJ Prikulis Ingrid I Leliveld S Rutger SR Lin Chi-Ying CY Ishizuka Koko K Sawa Akira A Ramos Adriana A Rosa Isaac I García Ángel Á Requena Jesús R JR Hipolito Maria M Rai Narayan N Nwulia Evaristus E Henning Uwe U Ferrea Stefano S Luckhaus Christian C Ekelund Jesper J Veijola Juha J Järvelin Marjo-Riitta MR Hennah William W Korth Carsten C

Human molecular genetics 20120713 20

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 antibod ...[more]

PMID: 22798627

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

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

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