Characterization of early psychosis patients carrying a genetic vulnerability to redox dysregulation: a computational analysis of mechanism-based gene expression profile in fibroblasts.

In view of its heterogeneity, schizophrenia needs new diagnostic tools based on mechanistic biomarkers that would allow early detection. Complex interaction between genetic and environmental risk factors may lead to NMDAR hypofunction, inflammation and redox dysregulation, all converging on oxidative stress. Using computational analysis, the expression of 76 genes linked to these systems, known to be abnormally regulated in schizophrenia, was studied in skin-fibroblasts from early psychosis patients and age-matched controls (N = 30), under additional pro-oxidant challenge to mimic environmental stress. To evaluate the contribution of a genetic risk related to redox dysregulation, we investigated the GAG trinucleotide polymorphism in the key glutathione (GSH) synthesizing enzyme, glutamate-cysteine-ligase-catalytic-subunit (gclc) gene, known to be associated with the disease. Patients and controls showed different gene expression profiles that were modulated by GAG-gclc genotypes in combination with oxidative challenge. In GAG-gclc low-risk genotype patients, a global gene expression dysregulation was observed, especially in the antioxidant system, potentially induced by other risks. Both controls and patients with GAG-gclc high-risk genotype (gclcGAG-HR) showed similar gene expression profiles. However, under oxidative challenge, a boosting of other antioxidant defense, including the master regulator Nrf2 and TRX systems was observed only in gclcGAG-HR controls, suggesting a protective compensation against the genetic GSH dysregulation. Moreover, RAGE (redox/inflammation interaction) and AGMAT (arginine pathway) were increased in the gclcGAG-HR patients, suggesting some additional risk factors interacting with this genotype. Finally, the use of a machine-learning approach allowed discriminating patients and controls with an accuracy up to 100%, paving the way towards early detection of schizophrenia.

Correction: MMP9/RAGE pathway overactivation mediates redox dysregulation and neuroinflammation, leading to inhibitory/excitatory imbalance: a reverse translation study in schizophrenia patients.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

MMP9/RAGE pathway overactivation mediates redox dysregulation and neuroinflammation, leading to inhibitory/excitatory imbalance: a reverse translation study in schizophrenia patients.

Various mechanisms involved in schizophrenia pathophysiology, such as dopamine dysregulation, glutamate/NMDA receptor dysfunction, neuroinflammation or redox imbalance, all appear to converge towards an oxidative stress "hub" affecting parvalbumine interneurones (PVI) and their perineuronal nets (PNN) (Lancet Psychiatry. 2015;2:258-70); (Nat Rev Neurosci. 2016;17:125-34). We aim to investigate underlying mechanisms linking oxidative stress with neuroinflammatory and their long-lasting harmful consequences. In a transgenic mouse of redox dysregulation carrying a permanent deficit of glutathione synthesis (gclm-/-), the anterior cingulate cortex presented early in the development increased oxidative stress which was prevented by the antioxidant N-acetylcysteine (Eur J Neurosci. 2000;12:3721-8). This oxidative stress induced microglia activation and redox-sensitive matrix metalloproteinase 9 (MMP9) stimulation, leading to the receptor for advanced glycation end-products (RAGE) shedding into soluble and nuclear forms, and subsequently to nuclear factor-kB (NF-kB) activation and secretion of various cytokines. Blocking MMP9 activation prevented this sequence of alterations and rescued the normal maturation of PVI/PNN, even if performed after an additional insult that exacerbated the long term PVI/PNN impairments. MMP9 inhibition thus appears to be able to interrupt the vicious circle that maintains the long-lasting deleterious effects of the reciprocal interaction between oxidative stress and neuroinflammation, impacting on PVI/PNN integrity. Translation of these experimental findings to first episode patients revealed an increase in plasma soluble RAGE relative to healthy controls. This increase was associated with low prefrontal GABA levels, potentially predicting a central inhibitory/excitatory imbalance linked to RAGE shedding. This study paves the way for mechanistically related biomarkers needed for early intervention and MMP9/RAGE pathway modulation may lead to promising drug targets.

Mutations in CEP78 Cause Cone-Rod Dystrophy and Hearing Loss Associated with Primary-Cilia Defects.

Cone-rod degeneration (CRD) belongs to the disease spectrum of retinal degenerations, a group of hereditary disorders characterized by an extreme clinical and genetic heterogeneity. It mainly differentiates from other retinal dystrophies, and in particular from the more frequent disease retinitis pigmentosa, because cone photoreceptors degenerate at a higher rate than rod photoreceptors, causing severe deficiency of central vision. After exome analysis of a cohort of individuals with CRD, we identified biallelic mutations in the orphan gene CEP78 in three subjects from two families: one from Greece and another from Sweden. The Greek subject, from the island of Crete, was homozygous for the c.499+1G>T (IVS3+1G>T) mutation in intron 3. The Swedish subjects, two siblings, were compound heterozygotes for the nearby mutation c.499+5G>A (IVS3+5G>A) and for the frameshift-causing variant c.633delC (p.Trp212Glyfs(∗)18). In addition to CRD, these three individuals had hearing loss or hearing deficit. Immunostaining highlighted the presence of CEP78 in the inner segments of retinal photoreceptors, predominantly of cones, and at the base of the primary cilium of fibroblasts. Interaction studies also showed that CEP78 binds to FAM161A, another ciliary protein associated with retinal degeneration. Finally, analysis of skin fibroblasts derived from affected individuals revealed abnormal ciliary morphology, as compared to that of control cells. Altogether, our data strongly suggest that mutations in CEP78 cause a previously undescribed clinical entity of a ciliary nature characterized by blindness and deafness but clearly distinct from Usher syndrome, a condition for which visual impairment is due to retinitis pigmentosa.

Timely N-Acetyl-Cysteine and Environmental Enrichment Rescue Oxidative Stress-Induced Parvalbumin Interneuron Impairments via MMP9/RAGE Pathway: A Translational Approach for Early Intervention in Psychosis.

Research in schizophrenia (SZ) emphasizes the need for new therapeutic approaches based on antioxidant/anti-inflammatory compounds and psycho-social therapy. A hallmark of SZ is a dysfunction of parvalbumin-expressing fast-spiking interneurons (PVI), which are essential for neuronal synchrony during sensory/cognitive processing. Oxidative stress and inflammation during early brain development, as observed in SZ, affect PVI maturation. We compared the efficacy of N-acetyl-cysteine (NAC) and/or environmental enrichment (EE) provided during juvenile and/or adolescent periods in rescuing PVI impairments induced by an additional oxidative insult during childhood in a transgenic mouse model with gluthation deficit (Gclm KO), relevant for SZ. We tested whether this rescue was promoted by the inhibition of MMP9/RAGE mechanism, both in the mouse model and in early psychosis (EP) patients, enrolled in a double-blind, randomized, placebo-controlled clinical trial of NAC supplementation for 6 months. We show that a sequential combination of NAC+EE applied after an early-life oxidative insult recovers integrity and function of PVI network in adult Gclm KO, via the inhibition of MMP9/RAGE. Six-month NAC treatment in EP patients reduces plasma sRAGE in association with increased prefrontal GABA, improvement of cognition and clinical symptoms, suggesting similar neuroprotective mechanisms. The sequential combination of NAC+EE reverses long-lasting effects of an early oxidative insult on PVI/perineuronal net (PNN) through the inhibition of MMP9/RAGE mechanism. In analogy, patients vulnerable to early-life insults could benefit from a combined pharmacological and psycho-social therapy.