Decreased Expression of α-Synuclein, Nogo-A and UCH-L1 in Patients with Schizophrenia: A Preliminary Serum Study

Demirel, Ömer Faruk; Çetin, İhsan; Turan, Şenol; Sağlam, Tarık; Yıldız, Nazım; Duran, Alaattin

doi:10.4306/pi.2017.14.3.344

Cited by 18 publications

(12 citation statements)

References 45 publications

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“…In addition, point mutations in the α-synuclein gene are known to be a risk factor for Parkinson’s disease 37. The association between α-synuclein expression and schizophrenia has been shown by a previous study 3839…”

Section: Introductionmentioning

confidence: 77%

<p>Evaluation of α-synuclein and apolipoprotein E as potential biomarkers in cerebrospinal fluid to monitor pharmacotherapeutic efficacy in dopamine dictated disease states of Parkinson’s disease and schizophrenia</p>

Gupta¹,

Pokhriyal²,

Das³

et al. 2019

NDT

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Background and objective Dopamine plays an important role in the disease pathology of Parkinson’s disease and schizophrenia. These two neuropsychiatric disorders represent disease end points of the dopaminergic spectrum where Parkinson’s disease represents dopamine deficit and schizophrenia represents dopamine hyperactivity in the mid-brain. Therefore, current treatment strategies aim to restore normal dopamine levels. However, during treatment patients develop adverse effects due to overshooting of physiological levels of dopamine leading to psychosis in Parkinson’s disease, and extrapyramidal symptoms in schizophrenia. Absence of any laboratory tests hampers modulation of pharmacotherapy. Apolipoprotein E and α-synuclein have an important role in the neuropathology of these two diseases. The objective of this study was to evaluate cerebrospinal fluid (CSF) concentrations of apolipoprotein E and α-synuclein in patients with these two diseases so that they may serve as biomarkers to monitor therapy in Parkinson’s disease and schizophrenia. Methods Drug-naïve Parkinson’s disease patients and Parkinson’s disease patients treated with dopaminergic therapy, neurological controls, schizophrenic patients treated with antidopaminergic therapy, and drug-naïve schizophrenic patients were recruited for the study and CSF was collected. Enzyme-linked immunosorbent assays were carried out to estimate the concentrations of apolipoprotein E and α-synuclein. Pathway analysis was done to establish a possible role of these two proteins in various pathways in these two dopamine dictated diseases. Results Apolipoprotein E and α-synuclein CSF concentrations have an inverse correlation along the entire dopaminergic clinical spectrum. Pathway analysis convincingly establishes a plausible hypothesis for their co-regulation in the pathogenesis of Parkinson’s disease and schizophrenia. Each protein by itself or as a combination has encouraging sensitivity and specificity values of more than 55%. Conclusion The dynamic variation of these two proteins along the spectrum is ideal for them to be pursued as pharmacotherapeutic biomarkers in CSF to monitor pharmacological efficacy in Parkinson’s disease and schizophrenia.

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Section: Introductionmentioning

confidence: 77%

<p>Evaluation of α-synuclein and apolipoprotein E as potential biomarkers in cerebrospinal fluid to monitor pharmacotherapeutic efficacy in dopamine dictated disease states of Parkinson’s disease and schizophrenia</p>

Gupta¹,

Pokhriyal²,

Das³

et al. 2019

NDT

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“…Whether alterations of this pathway are present in MS patients remains to be elucidated. Interestingly, several pathologies besides MS have been recently described to be associated with altered Nogo‐A levels, such as Alzheimer's disease and schizophrenia (Xu et al, 2015; Demirel et al, 2017); thus, patients with these diseases can benefit from the results of this study. Neutralization with anti‐Nogo‐A antibodies or inhibition of NgR1 with LINGO‐1 has already been evaluated in animal models and clinical trials for MS and show potential therapeutic effects (Ineichen et al, 2017).…”

Section: Discussionmentioning

confidence: 82%

Astrocytes as a target for Nogo‐A and implications for synapse formation in vitro and in a model of acute demyelination

Espírito-Santo

Coutinho

Dezonne

et al. 2021

Glia

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Central nervous system (CNS) function depends on precise synaptogenesis, which is shaped by environmental cues and cellular interactions. Astrocytes are outstanding regulators of synapse development and plasticity through contact‐dependent signals and through the release of pro‐ and antisynaptogenic factors. Conversely, myelin and its associated proteins, including Nogo‐A, affect synapses in a inhibitory fashion and contribute to neural circuitry stabilization. However, the roles of Nogo‐A‐astrocyte interactions and their implications in synapse development and plasticity have not been characterized. Therefore, we aimed to investigate whether Nogo‐A affects the capacity of astrocytes to induce synaptogenesis. Additionally, we assessed whether downregulation of Nogo‐A signaling in an in vivo demyelination model impacts the synaptogenic potential of astrocytes. Our in vitro data show that cortical astrocytes respond to Nogo‐A through RhoA pathway activation, exhibiting stress fiber formation and decreased ramified morphology. This phenotype was associated with reduced levels of GLAST protein and aspartate uptake, decreased mRNA levels of the synaptogenesis‐associated genes Hevin, glypican‐4, TGF‐β1 and BDNF, and decreased and increased protein levels of Hevin and SPARC, respectively. Corroborating these findings, conditioned medium from Nogo‐A‐treated astrocytes suppressed the formation of structurally and functionally mature synapses in cortical neuronal cultures. After cuprizone‐induced acute demyelination, we observed reduced immunostaining for Nogo‐A in the visual cortex accompanied by higher levels of Hevin expression in astrocytes and an increase in excitatory synapse density. Hence, we suggest that interactions between Nogo‐A and astrocytes might represent an important pathway of plasticity regulation and could be a target for therapeutic intervention in demyelinating diseases in the future.

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“…47 Although a PPI deficit is in line with the observed striatal hyperdopaminergia and locomotor hyperactivity, the 2 phenotypes developed differently with time, that is, increased dopamine/activity emerged at 3 months and PPI at 9 months, suggesting that additional neurotransmitter systems or factors play a role. Finally, few reports have revealed a link between AS and psychosis, irrespective of PD, including an association between SNCA polymorphisms and methamphetamine-induced psychosis, 48 decreased serum AS levels in schizophrenic patients, 49 and less frequent AS Lewy pathology in chronic schizophrenia compared with age-matched healthy elderly people. 50 Noteworthy are the small cohorts used in these clinical studies.…”

Section: Discussionmentioning

confidence: 99%

Psychosis‐Like Behavior and Hyperdopaminergic Dysregulation in Human α‐Synuclein BAC Transgenic Rats

et al. 2020

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A BS TRACT: Background: Parkinson's disease psychosis is a prevalent yet underreported and understudied nonmotor manifestation of Parkinson's disease and, arguably, the most debilitating. It is unknown if α-synuclein plays a role in psychosis, and if so, this endophenotype may be crucial for elucidating the neurodegenerative process. Objectives: We sought to dissect the underlying neurobiology of novelty-induced hyperactivity, reminiscent of psychosis-like behavior, in human α-synuclein BAC rats. Results: Herein, we demonstrate a prodromal psychosis-like phenotype, including late-onset sensorimotor gating disruption, striatal hyperdopaminergic signaling, and persistent novelty-induced hyperactivity (up to 18 months), albeit reduced baseline locomotor activity, that is augmented by d-amphetamine and reversed by classical and atypical antipsychotics. MicroRNAmediated α-synuclein downregulation in the ventral midbrain rescues the hyperactive phenotype and restores striatal dopamine levels. This phenotype is accompanied by an abundance of age-, brain region-and gene dosedependent aberrant α-synuclein, including hyperphosphorylation, C-terminal truncation, aggregation pathology, and mild nigral neurodegeneration (27%). Conclusions: Our findings demonstrate a potential role of α-synuclein in Parkinson's disease psychosis and provide evidence of region-specific perturbations prior to neurodegeneration phenoconversion. The reported phenotype coincides with the latest clinical findings that suggest a premotor hyperdopaminergic state may occur, while at the same time, premotor psychotic symptoms are increasingly being recognized.

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Decreased Expression of α-Synuclein, Nogo-A and UCH-L1 in Patients with Schizophrenia: A Preliminary Serum Study

Cited by 18 publications

References 45 publications

<p>Evaluation of α-synuclein and apolipoprotein E as potential biomarkers in cerebrospinal fluid to monitor pharmacotherapeutic efficacy in dopamine dictated disease states of Parkinson’s disease and schizophrenia</p>

<p>Evaluation of α-synuclein and apolipoprotein E as potential biomarkers in cerebrospinal fluid to monitor pharmacotherapeutic efficacy in dopamine dictated disease states of Parkinson’s disease and schizophrenia</p>

Astrocytes as a target for Nogo‐A and implications for synapse formation in vitro and in a model of acute demyelination

Psychosis‐Like Behavior and Hyperdopaminergic Dysregulation in Human α‐Synuclein BAC Transgenic Rats

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