A transcriptome based approach to predict candidate drug targets and drugs for Parkinson's disease using an <i>in vitro</i> 6-OHDA model

Yiğit, Esra Nur; Sönmez, Elif; Yüksel, İsa Öner; Kurnaz, Işıl Aksan; Çakır, Tunahan

doi:10.1039/d2mo00267a

Cited by 4 publications

(3 citation statements)

References 49 publications

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“…To ascertain whether human-derived TAAR1 undergoes alterations in PD, we retrieved pertinent data from the Gene Expression Omnibus (GEO) database that employed human cell samples. The data was retrieved for 16 samples from the GSE198009 within the GEO database [45], and the expression levels of TAAR1 were quantified in both the control group and the model group. Subsequently, SPSS 26.0 software was employed to conduct a differential analysis of the results.…”

Section: Data Acquisition and Analysismentioning

confidence: 99%

“…As anticipated, there was a discernible downregulation of Taar1 in the striatum of PD mice (Figure 5A). To ascertain whether human-derived TAAR1 undergoes alterations in PD, we consulted the GEO database, specifically the GSE198009 dataset, which contrasts the transcriptome data differences between an in vitro PD model, which was constructed by stimulating SH-SY5Y cells with 6-hydroxydopamine (6-OHDA), and a control group [45]. This dataset revealed a significant decrease in the expression of TAAR1 in the in vitro PD model (Figure 5B).…”

Section: Taar1 Mrna Was Down-regulated From the Ob To The Hypothalamu...mentioning

confidence: 99%

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A Pilot Study on a Possible Mechanism behind Olfactory Dysfunction in Parkinson’s Disease: The Association of TAAR1 Downregulation with Neuronal Loss and Inflammation along Olfactory Pathway

Zhang,

Hong,

Shi

et al. 2024

Brain Sciences

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Parkinson’s disease (PD) is characterized not only by motor symptoms but also by non-motor dysfunctions, such as olfactory impairment; the cause is not fully understood. Our study suggests that neuronal loss and inflammation in brain regions along the olfactory pathway, such as the olfactory bulb (OB) and the piriform cortex (PC), may contribute to olfactory dysfunction in PD mice, which might be related to the downregulation of the trace amine-associated receptor 1 (TAAR1) in these areas. In the striatum, although only a decrease in mRNA level, but not in protein level, of TAAR1 was detected, bioinformatic analyses substantiated its correlation with PD. Moreover, we discovered that neuronal death and inflammation in the OB and the PC in PD mice might be regulated by TAAR through the Bcl-2/caspase3 pathway. This manifested as a decrease of anti-apoptotic protein Bcl-2 and an increase of the pro-apoptotic protein cleaved caspase3, or through regulating astrocytes activity, manifested as the increase of TAAR1 in astrocytes, which might lead to the decreased clearance of glutamate and consequent neurotoxicity. In summary, we have identified a possible mechanism to elucidate the olfactory dysfunction in PD, positing neuronal damage and inflammation due to apoptosis and astrocyte activity along the olfactory pathway in conjunction with the downregulation of TAAR1.

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Section: Data Acquisition and Analysismentioning

confidence: 99%

Section: Taar1 Mrna Was Down-regulated From the Ob To The Hypothalamu...mentioning

confidence: 99%

A Pilot Study on a Possible Mechanism behind Olfactory Dysfunction in Parkinson’s Disease: The Association of TAAR1 Downregulation with Neuronal Loss and Inflammation along Olfactory Pathway

Zhang,

Hong,

Shi

et al. 2024

Brain Sciences

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“…High-throughput sequencing technology, also known as next-generation sequencing (NGS), is an important tool for detecting differentially expressed genes from two or more samples, offering fast monitoring, high accuracy, and wide coverage ( Borrageiro et al, 2018 ; Sertbas and Ulgen, 2018 ; Bersuker et al, 2019 ). In clinical settings, NGS technology is used to enhance the detection of pathogenic genes ( Schilter et al, 2023 ; Yigit et al, 2023 ). For instance, high-throughput technology can be employed to identify rare variants and candidate genes linked to familial and sporadic PD ( Kim J. Y. et al, 2023 ; Qin et al, 2023 ).…”

Section: Introductionmentioning

confidence: 99%

Uncovering ferroptosis in Parkinson’s disease via bioinformatics and machine learning, and reversed deducing potential therapeutic natural products

et al. 2023

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Objective: Ferroptosis, a novel form of cell death, is closely associated with excessive iron accumulated within the substantia nigra in Parkinson’s disease (PD). Despite extensive research, the underlying molecular mechanisms driving ferroptosis in PD remain elusive. Here, we employed a bioinformatics and machine learning approach to predict the genes associated with ferroptosis in PD and investigate the interactions between natural products and their active ingredients with these genes.Methods: We comprehensively analyzed differentially expressed genes (DEGs) for ferroptosis associated with PD (PDFerDEGs) by pairing 3 datasets (GSE7621, GSE20146, and GSE202665) from the NCBI GEO database and the FerrDb V2 database. A machine learning approach was then used to screen PDFerDEGs for signature genes. We mined the interacted natural product components based on screened signature genes. Finally, we mapped a network combined with ingredients and signature genes, then carried out molecular docking validation of core ingredients and targets to uncover potential therapeutic targets and ingredients for PD.Results: We identified 109 PDFerDEGs that were significantly enriched in biological processes and KEGG pathways associated with ferroptosis (including iron ion homeostasis, iron ion transport and ferroptosis, etc.). We obtained 29 overlapping genes and identified 6 hub genes (TLR4, IL6, ADIPOQ, PTGS2, ATG7, and FADS2) by screening with two machine learning algorithms. Based on this, we screened 263 natural product components and subsequently mapped the “Overlapping Genes-Ingredients” network. According to the network, top 5 core active ingredients (quercetin, 17-beta-estradiol, glycerin, trans-resveratrol, and tocopherol) were molecularly docked to hub genes to reveal their potential role in the treatment of ferroptosis in PD.Conclusion: Our findings suggested that PDFerDEGs are associated with ferroptosis and play a role in the progression of PD. Taken together, core ingredients (quercetin, 17-beta-estradiol, glycerin, trans-resveratrol, and tocopherol) bind well to hub genes (TLR4, IL6, ADIPOQ, PTGS2, ATG7, and FADS2), highlighting novel biomarkers for PD.

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Mangiferin alleviates 6-OHDA-induced Parkinson's disease by inhibiting AKR1C3 to activate Wnt signaling pathway

Huang,

Wang,

Huang

2024

Neuroscience Letters

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A transcriptome based approach to predict candidate drug targets and drugs for Parkinson's disease using an in vitro 6-OHDA model

Abstract: The most common treatment strategies for Parkinson’s disease (PD) aim to slow down the neurodegeneration process or control the symptoms. In this study, using an in vitro PD model we...

Cited by 4 publications

References 49 publications

A Pilot Study on a Possible Mechanism behind Olfactory Dysfunction in Parkinson’s Disease: The Association of TAAR1 Downregulation with Neuronal Loss and Inflammation along Olfactory Pathway

A Pilot Study on a Possible Mechanism behind Olfactory Dysfunction in Parkinson’s Disease: The Association of TAAR1 Downregulation with Neuronal Loss and Inflammation along Olfactory Pathway

Uncovering ferroptosis in Parkinson’s disease via bioinformatics and machine learning, and reversed deducing potential therapeutic natural products

Mangiferin alleviates 6-OHDA-induced Parkinson's disease by inhibiting AKR1C3 to activate Wnt signaling pathway

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