Dose-dependent expression of claudin-5 is a modifying factor in schizophrenia

Greene, Chris; Kealy, John; Humphries, Marian M.; Gong, Y.; Hou, Jianghui; Hudson, Natalie; Cassidy, Lara M.; Martiniano, Rui; Shashi, .; Hooper, Stephen R.; Grant, Gerald A.; Kenna, Paul F.; Norris, Karl; Callaghan, Charlotte K.; Islam, Monoarul; O’Mara, Shane M.; Najda, Zaneta; Campbell, Susan G.; Pachter, Joel S.; Thomas, Jay C.; Williams, Nigel; Humphries, Peter; Murphy, Kieran C.; Campbell, Matthew

doi:10.1038/mp.2017.156

Cited by 163 publications

(186 citation statements)

References 39 publications

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“…The cause of schizophrenia is not well-understood but may involve disturbed dopamine and NMDA receptor signaling. In keeping with a leaky BBB, the level of Cldn5, one of the proteins in the endothelial cell tight junctions in the BBB (see below), was reduced in schizophrenic patients [132]. Elevated levels of albumin in the CSF in schizophrenic patients indicate leakage across the BBB [131].…”

Section: Neurodegenerative Diseases and The Brain Vasculature-an Emermentioning

confidence: 97%

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Emerging links between cerebrovascular and neurodegenerative diseases—a special role for pericytes

2019

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Neurodegenerative and cerebrovascular diseases cause considerable human suffering, and therapy options for these two disease categories are limited or non-existing. It is an emerging notion that neurodegenerative and cerebrovascular diseases are linked in several ways, and in this review, we discuss the current status regarding vascular dysregulation in neurodegenerative disease, and conversely, how cerebrovascular diseases are associated with central nervous system (CNS) degeneration and dysfunction. The emerging links between neurodegenerative and cerebrovascular diseases are reviewed with a particular focus on pericytes-important cells that ensheath the endothelium in the microvasculature and which are pivotal for blood-brain barrier function and cerebral blood flow. Finally, we address how novel molecular and cellular insights into pericytes and other vascular cell types may open new avenues for diagnosis and therapy development for these important diseases.

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Section: Neurodegenerative Diseases and The Brain Vasculature-an Emermentioning

confidence: 97%

“…Elevated levels of albumin in the CSF in schizophrenic patients indicate leakage across the BBB [131]. In keeping with a leaky BBB, the level of Cldn5, one of the proteins in the endothelial cell tight junctions in the BBB (see below), was reduced in schizophrenic patients [132].…”

Section: Neurodegenerative Diseases and The Brain Vasculature-an Emermentioning

confidence: 97%

Emerging links between cerebrovascular and neurodegenerative diseases—a special role for pericytes

2019

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“…The case for BBB disruption in TBI is strong [53][54][55], with a biphasic opening of the BBB believed to be part of the symptoms underlying the neurological effects observed following TBI [56]. Similarly, the dynamism of the BBB appears to be related to changes in neuronal firing during epilepsy [57][58][59][60].…”

Section: Associations Between the Bbb And Neuropsychiatric Disordersmentioning

confidence: 99%

“…It has been observed in a number of populations that there is a weak genetic association between claudin-5 and the development of schizophrenia, in particular the allele rs10314 has been singled out as being a potential risk factor for psychosis [124][125][126][127][128] but this may be population-specific as the association was not replicated in a Japanese population [129]. rs10314 is a single nucleotide polymorphism (SNP) that produces only about half of the amount of protein as the wild type claudin-5 gene [57], meaning that individuals with that allele may be producing less claudin-5 than is typical. The effect of this allele is particularly striking in 22q11 deletion syndrome (22q11DS).…”

Section: Tight Junction Dysfunction In Schizophreniamentioning

confidence: 99%

“…Interestingly, claudin-5 lies within the deleted region in 22q11DS, meaning that individuals are haploinsufficient for claudin-5 and therefore only producing 50% as much claudin-5 compared to the normal population. Recently, we have shown that there is a significant association between the rs10314 variant and a diagnosis of schizophrenia in 22q11DS [57], suggesting that these individuals are producing only about 25% as much claudin-5 compared to the normal population and therefore may have greater BBB permeability. Support for the role of claudin-5 in schizophrenia also comes from preclinical work, where antipsychotic drugs have been shown to directly increase claudin-5 expression in vitro and in vivo [57].…”

Section: Tight Junction Dysfunction In Schizophreniamentioning

confidence: 99%

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Blood-brain barrier regulation in psychiatric disorders

Kealy

Greene

Campbell

2020

Neuroscience Letters

197

135

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The blood-brain barrier (BBB) is a dynamic interface between the peripheral blood supply and the cerebral parenchyma, controlling the transport of material to and from the brain. Tight junctions between the endothelial cells of the cerebral microvasculature limit the passage of large, negatively charged molecules via paracellular diffusion whereas transcellular transportation across the endothelial cell is controlled by a number of mechanisms including transporter proteins, endocytosis, and diffusion. Here, we review the evidence that perturbation of these processes may underlie the development of psychiatric disorders including schizophrenia, autism spectrum disorder (ASD), and affective disorders. Increased permeability of the BBB appears to be a common factor in these disorders, leading to increased infiltration of peripheral material into the brain culminating in neuroinflammation and oxidative stress. However, although there is no common mechanism underpinning BBB dysfunction even within each particular disorder, the tight junction protein claudin-5 may be a clinically relevant target given that both clinical and pre-clinical research has linked it to schizophrenia, ASD, and depression. Additionally, we discuss the clinical significance of the BBB in diagnosis (genetic markers, dynamic contrast-enhanced-magnetic resonance imaging, and blood biomarkers) and in treatment (drug delivery).

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Association of Mitochondrial Biogenesis With Variable Penetrance of Schizophrenia

Tran

Crowley

et al. 2021

JAMA Psychiatry

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that underlie variable penetrance for neuropsychiatric illness in the context of genetic variants that carry elevated risk can advance novel treatment approaches for these disorders.OBJECTIVE To test the hypothesis that mitochondrial compensation is associated with the variable penetrance of schizophrenia in the 22q11.2 deletion syndrome (22q11DS). DESIGN, SETTING, AND PARTICIPANTSThis case-control study compared measures of mitochondrial function and the expression of related genes in 14 induced pluripotent stem cell-derived neurons from typically developing control individuals (6 lines) and from adults with 22q11DS (8 lines). The individuals with 22q11DS included 2 groups, those carrying a diagnosis of schizophrenia and those without this diagnosis (4 lines each). Similar measures were made of lymphoblastic cells lines (LCLs) from a separate group of adults with 22q11DS with (10 lines) or without (8 lines) schizophrenia. The study included samples derived from a clinical setting. The induced pluripotent stem cell lines were derived from individuals with 22q11DS with or without a diagnosis of schizophrenia at Stanford University. The LCLs were from adults within the 22q and You Center at the Children's Hospital of Philadelphia. Data were analyzed between July 1, 2019, and January 24, 2021.MAIN OUTCOMES AND MEASURES Total adenosine triphosphate (ATP), oxidative phosphorylation (OXPHOS) complex activity, and messenger RNA expression via reverse transcription-polymerase chain reaction of selected genes encoding for mitochondrial proteins.RESULTS Study participants included men and women aged 18 to 37 years. Of 32 participants, the mean (SD) age of men was 27 (1.9) years and of women was 29 (1.2) years. Replicating a previous study, neurons from the 22q11DS and schizophrenia (22q+Sz) group had reduced ATP levels (mean [SD], 15.6 [1.5] vs 21.9 [1.4]; P = .02) and reduced OXPHOS activity (ie, complex I; 1.51 [0.1] vs 1.89 [0.1]; P = .01). These deficits were not present in neurons from individuals with 22q11DS without schizophrenia (22q[−]Sz). In this group, the expression of multiple genes encoding OXPHOS subunits was significantly upregulated. For example, compared with control individuals, NDUFV2 expression was increased by 50% in the 22q(−)Sz group (P < .001) but not significantly changed in the 22q+Sz group. Expression of genes driving mitochondrial biogenesis, including PGC1α, showed a similar pattern of upregulation in the 22q(−)Sz group compared with the control and the 22q+Sz groups. Stimulation of mitochondrial biogenesis normalizes the ATP deficit seen in 22q+Sz neurons. Finally, using LCLs from a separate group of adults with 22q11DS, evidence for enhanced mitochondrial biogenesis was again found in the 22q(−)Sz group. CONCLUSIONS AND RELEVANCEIn this study, an increase in mitochondrial biogenesis and function was associated with the absence of schizophrenia in neurons and LCLs from individuals with 22q11DS, but the deficit in the 22q+Sz group was reversible by agents that enhance mitochondrial biogenesis....

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Dose-dependent expression of claudin-5 is a modifying factor in schizophrenia

Cited by 163 publications

References 39 publications

Emerging links between cerebrovascular and neurodegenerative diseases—a special role for pericytes

Emerging links between cerebrovascular and neurodegenerative diseases—a special role for pericytes

Blood-brain barrier regulation in psychiatric disorders

Association of Mitochondrial Biogenesis With Variable Penetrance of Schizophrenia

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