Proteomic, genomic and translational approaches identify CRMP1 for a role in schizophrenia and its underlying traits.
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.
Department of Neuropathology, Heinrich Heine University Düsseldorf, Germany.
Verian
V
Bader
Liisa
L
Tomppo
Svenja V
SV
Trossbach
Nicholas J
NJ
Bradshaw
Ingrid
I
Prikulis
S Rutger
SR
Leliveld
Chi-Ying
CY
Lin
Koko
K
Ishizuka
Akira
A
Sawa
Adriana
A
Ramos
Isaac
I
Rosa
Ángel
Á
García
Jesús R
JR
Requena
Maria
M
Hipolito
Narayan
N
Rai
Evaristus
E
Nwulia
Uwe
U
Henning
Stefano
S
Ferrea
Christian
C
Luckhaus
Jesper
J
Ekelund
Juha
J
Veijola
Marjo-Riitta
MR
Järvelin
William
W
Hennah
Carsten
C
Korth
D000328:Adult; D000818:Animals; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D015331:Cohort Studies; D020022:Genetic Predisposition to Disease; D023281:Genomics; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D020543:Proteome / Q000235:genetics / Q000378:metabolism*; D040901:Proteomics; D000091042:Reelin Protein; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D000098855:Collapsin Response Mediator Protein 1
D009419:Nerve Tissue Proteins; D020543:Proteome; D000091042:Reelin Protein; C102924:CRMP1 protein, human; D000098855:Collapsin Response Mediator Protein 1; C412476:DISC1 protein, human; C498794:Disc1 protein, mouse; C000717127:RELN protein, human; C000717128:Reln protein, mouse