TY - JOUR
T1 - Proteomic, genomic and translational approaches identify CRMP1 for a role in schizophrenia and its underlying traits
AU - Bader, Verian
AU - Tomppo, Liisa
AU - Trossbach, Svenja V.
AU - Bradshaw, Nicholas J.
AU - Prikulis, Ingrid
AU - Rutger Leliveld, S.
AU - Lin, Chi Ying
AU - Ishizuka, Koko
AU - Sawa, Akira
AU - Ramos, Adriana
AU - Rosa, Isaac
AU - García, Ångel
AU - Requena, Jesús R.
AU - Hipolito, Maria
AU - Rai, Narayan
AU - Nwulia, Evaristus
AU - Henning, Uwe
AU - Ferrea, Stefano
AU - Luckhaus, Christian
AU - Ekelund, Jesper
AU - Veijola, Juha
AU - Järvelin, Marjo Riitta
AU - Hennah, William
AU - Korth, Carsten
N1 - Funding Information:
U.H., S.F., C.L. and, independently, V.B. are supported by grants of the Forschungskommission of the Medical Faculty of the University of Düsseldorf. L.T. is supported by the Jalmari and Rauha Ahokas Foundation. W.H. is supported by the Academy of Finland (Postdoctoral Fellowship: 128504). N.J.B. is supported by a fellowship from the Alexander von Humboldt Foundation, Germany.
Funding Information:
Funding for this research was obtained from the SMRI (02R-186, Baltimore, MD, USA) and the DFG (Ko 1679/ 3-1; GRK1033) to C.K., ERANET-NEURON (DISCover, BMBF 01EW1003 and ISCIII PI09/2688, respectively) to C.K. and J.R.R., USPHS grants (MH-084018, MH-094268 Silvio O. Conte Center, MH-069853, MH-085226, MH-088753 and MH-092443 to A.S.; MH-091460 to E.N. and A.S.); a grants from DANA, RUSK, S-R foundations, NARSAD and MSCRF to A.S.; grant from DANA Foundation to E.N.
PY - 2012/10
Y1 - 2012/10
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=84867118143&partnerID=8YFLogxK
U2 - 10.1093/hmg/dds273
DO - 10.1093/hmg/dds273
M3 - Article
C2 - 22798627
AN - SCOPUS:84867118143
SN - 0964-6906
VL - 21
SP - 4406
EP - 4418
JO - Human molecular genetics
JF - Human molecular genetics
IS - 20
M1 - dds273
ER -