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.

Disrupted in Schizophrenia 1 regulates the processing of reelin in the perinatal cortex

“…Such links between DISC1 and reelin have been hypothesised previously (Deutsch et al, 2010;Bader et al, 2012), and the two proteins share several common pathway elements, which are known to include LIS1, GSK3β, Akt and APP (Assadi et al, 2003;Ohkubo et al, 2003;Brandon et al, 2004;Hashimoto et al, 2006;Jossin and Goffinet, 2007;Hoe et al, 2009;Mao et al, 2009;Young-Pearse et al, 2010). Our results, however show, for the first time a direct functional link between DISC1 and reelin, with DISC1 found to alter the post-translational regulation of reelin by proteolytic cleavage.…”

CRMPs: critical molecules for neurite morphogenesis and neuropsychiatric diseases

“…Recent studies of gene copy number variants and exome sequencing of single-nucleotide polymorphisms (SNPs) implicate genes modulating cytoskeleton proteins, NMDA receptors and VGCCs, converging on pathways regulating synaptic plasticity. 55 It is not surprising that CRMP1, also called dihydropyriminidase-like 1 (DPYSL1), which interacts with reelin and DISC1, 18 and CRMP2 (DPYSL2), which affects not only neurites but also neurotransmitter release and modulates Ca 2+ fluxes through activation of NMDA receptors, 28 have been included in the list of schizophrenia susceptibility genes. CRMP1 was identified as altered protein in a search for schizophreniaspecific epitopes from patients' post-mortem brain fractions.…”

Proteomic Characterization of the Brain and Cerebrospinal Fluid of Schizophrenia Patients

“…Another gene, CRMP1 (collapsin response mediator protein 1), which is dependent on DISC1, is also related to anhedonia. In this multidisciplinary study, it was shown that in lymphoblastoid cell lines of schizophrenia patients there was an increase in CRMP1 expression, suggesting a potential role of a bloodbased diagnostic marker [91]. Another DISC1-related gene was downregulated in CSF of schizophrenia patients, namely CCDC3 (coiledcoil domain-containing protein 3 precursor) [58].…”

“…Besides, animal models of DISC1-related diseases displayed anhedonia-like behavior, indicated by immobility in the forced swimming test. Impairment of this gene has been related to disrupted axonal transport in neurons [91]. Another gene, CRMP1 (collapsin response mediator protein 1), which is dependent on DISC1, is also related to anhedonia.…”