New genes associated with schizophrenia in neurite formation: a review of cell culture experiments

Bellon, Alfredo

doi:10.1038/sj.mp.4001985

Cited by 66 publications

(61 citation statements)

References 168 publications

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“…Defective neuritogenesis is the most consistent neuroanatomical finding in post-mortem studies of schizophrenia (Black et al, 2004;Guidotti et al, 2000;Glantz and Lewis, 2000) and in functional studies using animal models Ozeki et al, 2003;Bellon, 2007). Recently, two studies using induced pluripotent stem cell techniques showed that neurons derived from fibroblasts of human schizophrenia patients had reduced neurite numbers and neuronal connectivity (Brennand et al, 2011;Chiang et al, 2011).…”

Section: Discussionmentioning

confidence: 97%

Recurrent deletions of ULK4 in schizophrenia: a novel gene crucial for neuritogenesis and neuronal motility

Luo

Hunter

et al. 2013

Journal of Cell Science

121

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Although many pathogenic copy number variations (CNVs) are associated with neuropsychiatric diseases, few of them have been functionally characterised. Here we report multiple schizophrenia cases with CNV abnormalities specific to unc-51-like kinase 4 (ULK4), a serine/threonine kinase gene. Deletions spanning exons 21-34 of ULK4 were present in 4 out of 3391 schizophrenia patients from the International Schizophrenia Consortium, but absent in 3181 controls. Deletions removing exons 33 and 34 of the large splice variant of ULK4 also were enriched in Icelandic schizophrenia and bipolar patients compared with 98,022 controls (P50.0007 for schizophrenia plus bipolar disorder). Combining the two cohorts gives a P-value less than 0.0001 for schizophrenia, or for schizophrenia plus bipolar disorder. The expression of ULK4 is neuron-specific and developmentally regulated. ULK4 modulates multiple signalling pathways that include ERK, p38, PKC and JNK, which are involved in stress responses and implicated in schizophrenia. Knockdown of ULK4 disrupts the composition of microtubules and compromises neuritogenesis and cell motility. Targeted Ulk4 deletion causes corpus callosum agenesis in mice. Our findings indicate that ULK4 is a rare susceptibility gene for schizophrenia.

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Section: Discussionmentioning

confidence: 97%

Recurrent deletions of ULK4 in schizophrenia: a novel gene crucial for neuritogenesis and neuronal motility

Luo

Hunter

et al. 2013

Journal of Cell Science

121

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“…Several genes such as NRG-1, Akt1 and DISC have been shown to confer susceptibility for SCZ and proteins encoded by these genes are implicated in neurite formation in cellular and animal models of neurodevelopment. 74 In addition, the synaptic proteins VAMP-2 and SNAP-25 have demonstrated expression changes in SCZ and BPD and are also involved in neurite elongation and sprouting. 75 Further expression studies of proteins involved in neurite formation in these diseases are required to strengthen a hypothesis such as this.…”

Section: Discussionmentioning

confidence: 99%

Proteomic analysis of membrane microdomain-associated proteins in the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder reveals alterations in LAMP, STXBP1 and BASP1 protein expression

et al. 2008

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The dorsolateral prefrontal cortex (dlpfc) is strongly implicated in the pathogenesis of schizophrenia (SCZ) and bipolar disorder (BPD) and, within this region, abnormalities in glutamatergic neurotransmission and synaptic function have been described. Proteins associated with these functions are enriched in membrane microdomains (MM). In the current study, we used two complementary proteomic methods, two-dimensional difference gel electrophoresis and one-dimensional sodium dodecyl sulphate polyacrylamide gel electrophoresis followed by reverse phase-liquid chromatography-tandem mass spectrometry (RP-LC-MS/MS) (gel separation liquid chromatography-tandem mass spectrometry (GeLC-MS/MS)) to assess protein expression in MM in pooled samples of dlpfc from SCZ, BPD and control cases (n = 10 per group) from the Stanley Foundation Brain series. We identified 16 proteins altered in one/both disorders using proteomic methods. We selected three proteins with roles in synaptic function (syntaxin-binding protein 1 (STXBP1), brain abundant membrane-attached signal protein 1 (BASP1) and limbic system-associated membrane protein (LAMP)) for validation by western blotting. This revealed significantly increased expression of these proteins in SCZ (STXBP1 (24% difference; P < 0.001), BASP1 (40% difference; P < 0.05) and LAMP (22% difference; P < 0.01)) and BPD (STXBP1 (31% difference; P < 0.001), BASP1 (23% difference; P < 0.01) and LAMP (20% difference; P < 0.01)) in the Stanley brain series (n = 20 per group). Further validation in dlpfc from the Harvard brain subseries (n = 10 per group) confirmed increased protein expression in SCZ of STXBP1 (18% difference; P < 0.0001), BASP1 (14% difference; P < 0.0001) but not LAMP (20% difference; P = 0.14). No significant differences in STXBP1, BASP1 or LAMP protein expression in BPD dlpfc were observed. This study, through proteomic assessments of MM in dlpfc and validation in two brain series, strongly implicates LAMP, STXBP1 and BASP1 in SCZ and supports the view of a neuritic and synaptic dysfunction in the neuropathology of SCZ.

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“…The examination of different haplotypes of Akt, the most important downstream target of PI3K revealed mostly positive results [168,[176][177][178], however, also weak positive [175] and negative data exist [82,179]. In the light of the recent replications, the evidence for Akt as a susceptibility gene for schizophrenia is encouraging and warrants further investigation [173,175].…”

Section: Linking Phosphatidylinositide 3-kinase (Pi3k) Pathway To Schmentioning

confidence: 95%

“…Downstream targets of PI3K are V-akt murine thymoma viral oncogene homologue (Akt), glycogen synthase kinase (GSK3Beta), Beta Catenin and CREB, which had all been involved in the pathophysiology of the disease based on protein, mRNA and enzyme activity changes [168,[170][171][172]. Increased apoptosis due to abnormalities in Akt signaling could contribute to the pathophysiology of schizophrenia [173][174][175]. The examination of different haplotypes of Akt, the most important downstream target of PI3K revealed mostly positive results [168,[176][177][178], however, also weak positive [175] and negative data exist [82,179].…”

Section: Linking Phosphatidylinositide 3-kinase (Pi3k) Pathway To Schmentioning

confidence: 99%

Molecular Mechanisms of Schizophrenia

Lang¹,

Puls²,

Müller³

et al. 2007

Cell Physiol Biochem

251

165

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Schizophrenia is a complex disorder, where family, twin and adoption studies have been demonstrating a high heritability of the disease and that this disease is not simply defined by several major genes but rather evolves from addition or potentiation of a specific cluster of genes, which subsequently determines the genetic vulnerability of an individual. Linkage and association studies suggest that a genetic vulnerablility, is not forcefully leading to the disease since triggering factors and environmental influences, i.e. birth complications, drug abuse, urban background or time of birth have been identified. This has lead to the assumption that schizophrenia is not only a genetically defined static disorder but a dynamic process leading to dysregulation of multiple pathways. There are several different hypothesis based on several facets of the disease, some of them due to the relatively well-known mechanisms of therapeutic agents. The most widely considered neurodevelopmental hypothesis of schizophrenia integrates environmental influences and causative genes. The dopamine hypothesis of schizophrenia is based on the fact that all common treatments involve antidopaminergic mechanisms and genes such as DRD2, DRD3, DARPP-32, BDNF or COMT are closely related to dopaminergic system functioning. The glutamatergic hypothesis of schizophrenia lead recently to a first successful mGlu2/3 receptor agonistic drug and is underpinned by significant findings in genes regulating the glutamatergic system (SLC1A6, SLC1A2 GRIN1, GRIN2A, GRIA1, NRG1, ErbB4, DTNBP1, DAAO, G72/30, GRM3). Correspondingly, GABA has been proposed to modulate the pathophysiology of the disease which is represented by the involvement of genes like GABRA1, GABRP, GABRA6 and Reelin. Moreover, several genes implicating immune, signaling and networking deficits have been reported to be involved in the disease, i.e. DISC1, RGS4, PRODH, DGCR6, ZDHHC8, DGCR2, Akt, CREB, IL-1B, IL-1RN, IL-10, IL-1B. However, molecular findings suggest that a complex interplay between receptors, kinases, proteins and hormones is involved in schizophrenia. In a unifying hypothesis, different cascades merge into another that ultimately lead to the development of symptoms adherent to schizophrenic disorders.

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New genes associated with schizophrenia in neurite formation: a review of cell culture experiments

Cited by 66 publications

References 168 publications

Recurrent deletions of ULK4 in schizophrenia: a novel gene crucial for neuritogenesis and neuronal motility

Recurrent deletions of ULK4 in schizophrenia: a novel gene crucial for neuritogenesis and neuronal motility

Proteomic analysis of membrane microdomain-associated proteins in the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder reveals alterations in LAMP, STXBP1 and BASP1 protein expression

Molecular Mechanisms of Schizophrenia

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