Ingenuity pathway analysis of α-synuclein predicts potential signaling pathways, network molecules, biological functions, and its role in neurological diseases

Kumar, Sunita; Lee, Sang Yoon

doi:10.3389/fnmol.2022.1029682

Cited by 5 publications

(1 citation statement)

References 43 publications

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“…IPA uses a network generation algorithm to segment the network map between molecules into multiple networks. In the next step, Molecule Activity Predictor (MAP) analysis filter was applied to predict the role of drugs in molecular activation or inhibition [ 40 ].…”

Section: Methodsmentioning

confidence: 99%

Prdx5 in the Regulation of Tuberous Sclerosis Complex Mutation-Induced Signaling Mechanisms

Bovari-Biri

Abdelwahab

Garai

et al. 2023

Cells

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(1) Background: Tuberous sclerosis complex (TSC) mutations directly affect mTORC activity and, as a result, protein synthesis. In several cancer types, TSC mutation is part of the driver mutation panel. TSC mutations have been associated with mitochondrial dysfunction, tolerance to reactive oxygen species due to increased thioredoxin reductase (TrxR) enzyme activity, tolerance to endoplasmic reticulum (ER) stress, and apoptosis. The FDA-approved drug rapamycin is frequently used in clinical applications to inhibit protein synthesis in cancers. Recently, TrxR inhibitor auranofin has also been involved in clinical trials to investigate the anticancer efficacy of the combination treatment with rapamycin. We aimed to investigate the molecular background of the efficacy of such drug combinations in treating neoplasia modulated by TSC mutations. (2) Methods: TSC2 mutant and TSC2 wild-type (WT) cell lines were exposed to rapamycin and auranofin in either mono- or combination treatment. Mitochondrial membrane potential, TrxR enzyme activity, stress protein array, mRNA and protein levels were investigated via cell proliferation assay, electron microscopy, etc. (3) Results: Auranofin and rapamycin normalized mitochondrial membrane potential and reduced proliferation capacity of TSC2 mutant cells. Database analysis identified peroxiredoxin 5 (Prdx5) as the joint target of auranofin and rapamycin. The auranofin and the combination of the two drugs reduced Prdx5 levels. The combination treatment increased the expression of heat shock protein 70, a cellular ER stress marker. (4) Conclusions: After extensive analyses, Prdx5 was identified as a shared target of the two drugs. The decreased Prdx5 protein level and the inhibition of both TrxR and mTOR by rapamycin and auranofin in the combination treatment made ER stress-induced cell death possible in TSC2 mutant cells.

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Section: Methodsmentioning

confidence: 99%

Prdx5 in the Regulation of Tuberous Sclerosis Complex Mutation-Induced Signaling Mechanisms

Bovari-Biri

Abdelwahab

Garai

et al. 2023

Cells

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The Role of Alpha-Synuclein Pathology

Fu,

Tanglay,

et al. 2024

Neuromethods

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Alpha-synuclein (αSyn) is a conformationally flexible protein that is known to be involved in key neuronal biological processes and the pathogenesis of Parkinson’s disease (PD). The aggregation of αSyn in the brain is not only the neuropathological hallmark of PD but also characterizes other primary synucleinopathies, including dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). These disorders share common clinical motor symptoms, namely, parkinsonism, which is associated with the loss of nigral dopaminergic neurons. Pathologically the selective neurodegeneration in synucleinopathies is linked to αSyn dysfunction and its abnormal interactions with other proteins. It should be noted that the aggregation of αSyn is not an absolute pathogenic cause for clinically or genetically diagnosed PD, as a minority of patients have substantial loss of nigral dopaminergic neurons in the absence of αSyn pathology. In addition, αSyn pathology is a commonly observed autopsy finding in asymptomatic senescent brains, confirming that αSyn pathology can occur independently of parkinsonism. Presently, there is no causative treatment for synucleinopathies; therefore, targeting αSyn remains the key research focus. Despite the importance of αSyn in the pathology of synucleinopathies, there is no consensus on reliable markers for defining toxic pathogenic αSyn aggregates in postmortem human brain tissue or on any critical αSyn-inducing pathological events. As such, there is an urgent need to establish a panel of antibodies and animal models for studying synucleinopathies. This chapter summarizes the traditional and recently developed methodologies in the field with suggestions on toolkits to assess the role of αSyn pathology.

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Xiaohuafuning Tang Intervenes Liver-Depression-and-Spleen-Deficiency Syndrome Chronic-Atrophic-Gastritis by Reshaping Amino Acid Metabolism Through Gut Microbiota

Chen,

Xu,

Wang

et al. 2024

Phytomedicine

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Ingenuity pathway analysis of α-synuclein predicts potential signaling pathways, network molecules, biological functions, and its role in neurological diseases

Cited by 5 publications

References 43 publications

Prdx5 in the Regulation of Tuberous Sclerosis Complex Mutation-Induced Signaling Mechanisms

Prdx5 in the Regulation of Tuberous Sclerosis Complex Mutation-Induced Signaling Mechanisms

The Role of Alpha-Synuclein Pathology

Xiaohuafuning Tang Intervenes Liver-Depression-and-Spleen-Deficiency Syndrome Chronic-Atrophic-Gastritis by Reshaping Amino Acid Metabolism Through Gut Microbiota

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