{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T08:39:56Z","timestamp":1765183196536,"version":"3.46.0"},"reference-count":105,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,12,7]],"date-time":"2025-12-07T00:00:00Z","timestamp":1765065600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100019345","name":"King Salman Center for Disability Research","doi-asserted-by":"publisher","award":["KSRG-2024-120"],"award-info":[{"award-number":["KSRG-2024-120"]}],"id":[{"id":"10.13039\/501100019345","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Parkinson\u2019s disease (PD) is a complex neurodegenerative disorder in aged people with multifaceted molecular underpinnings. It poses a severe threat to millions of older adults worldwide. The understanding of the molecular mechanisms of PD development and the performance of its therapeutic strategies has not yet reached a satisfactory level. Methods: This study integrated six transcriptomic datasets to uncover key genes (KGs) and their underlying pathogenic mechanisms, providing insights into potential therapeutic strategies for PD. We designed a comprehensive computational pipeline using various bioinformatics tools and databases to investigate PD-causing KGs, focusing on their functions, pathways, regulatory mechanisms, and potential therapeutic drug molecules. Results: In order to explore PD-causing KGs, we initially identified 303 differentially expressed genes (DEGs) between PD and control samples with 204 upregulated and 99 downregulated DEGs using the LIMMA approach with threshold values at Adj. p-value &lt; 0.05 and abs (log2FC) \u2265 1.0. Then, protein\u2013protein interaction (PPI) network analysis pinpointed seven top-ranked DEGs (GAPDH, PTEN, CCND1, APOE, ESR1, MAPK3\/ERK1, and SNCA) as KGs or central modulators of PD pathogenesis. Regulatory network analysis of KGs identified 3 top-ranked transcription factors (FOXC1, NFKB1, and TFAP2A) and 6 microRNAs (hsa-let-7b-5p, hsa-mir-16-5p, and others) as the pivotal regulators of KGs. Gene Ontology (GO) terms and KEGG pathway enrichment analyses with KGs revealed several crucial biological processes, molecular functions, cellular components, and neurodegenerative pathways associated with the development of PD. Finally, the top five molecules guided by KGs (Nilotinib, Bromocriptine, Withaferin-A, Celastrol, and Donepezil) were identified as promising drug candidates against PD and validated computationally through ADME\/T analysis and molecular dynamics simulation studies. Conclusions: The findings of this study may serve as valuable resources for developing effective treatment strategies for PD patients.<\/jats:p>","DOI":"10.3390\/genes16121459","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T08:21:43Z","timestamp":1765182103000},"page":"1459","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multi-Transcriptome-Informed Network Pharmacology Reveals Novel Biomarkers and Therapeutic Candidates for Parkinson\u2019s Disease"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-9061-8549","authenticated-orcid":false,"given":"Md. Al Amin","family":"Pappu","sequence":"first","affiliation":[{"name":"Bioinformatics Lab (Dry), Department of Statistics, University of Rajshahi, Rajshahi 6205, Bangladesh"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7993-3863","authenticated-orcid":false,"given":"Md.","family":"Alamin","sequence":"additional","affiliation":[{"name":"Department of Mathematics and Physics, School of Engineering & Physical Sciences, North South University, Dhaka 1229, Bangladesh"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Md Al","family":"Noman","sequence":"additional","affiliation":[{"name":"Bioinformatics Lab (Dry), Department of Statistics, University of Rajshahi, Rajshahi 6205, Bangladesh"},{"name":"Department of Statistics, University of Barishal, Barishal 8254, Bangladesh"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Most. Humaira","family":"Sultana","sequence":"additional","affiliation":[{"name":"Department of Management, School of Business & Economics, North South University, Dhaka 1229, Bangladesh"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Md. Foysal","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Bioinformatics Lab (Dry), Department of Statistics, University of Rajshahi, Rajshahi 6205, Bangladesh"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Md. Sanoar","family":"Hossain","sequence":"additional","affiliation":[{"name":"Bioinformatics Lab (Dry), Department of Statistics, University of Rajshahi, Rajshahi 6205, Bangladesh"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Md. Abdul","family":"Latif","sequence":"additional","affiliation":[{"name":"Bioinformatics Lab (Dry), Department of Statistics, University of Rajshahi, Rajshahi 6205, Bangladesh"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9082-2350","authenticated-orcid":false,"given":"Md. Fahim","family":"Faysal","sequence":"additional","affiliation":[{"name":"Department of Computer Science and Engineering (CSE), Rajshahi University of Engineering and Technology (RUET), Rajshahi 6203, Bangladesh"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"AKM","family":"Azad","sequence":"additional","affiliation":[{"name":"Department of Mathematics and Statistics, Faculty of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 13318, Saudi Arabia"},{"name":"Research Department, King Salman Center for Disability Research, Riyadh 11614, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5507-9399","authenticated-orcid":false,"given":"Salem A.","family":"Alyami","sequence":"additional","affiliation":[{"name":"Department of Mathematics and Statistics, Faculty of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 13318, Saudi Arabia"},{"name":"Research Department, King Salman Center for Disability Research, Riyadh 11614, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naif","family":"Alotaibi","sequence":"additional","affiliation":[{"name":"Department of Mathematics and Statistics, Faculty of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 13318, Saudi Arabia"},{"name":"Research Department, King Salman Center for Disability Research, Riyadh 11614, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3883-3396","authenticated-orcid":false,"given":"Md. 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Psychiatry Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e1986","DOI":"10.1212\/WNL.0000000000012826","article-title":"Trends in Mortality from Parkinson Disease in the United States, 1999\u20132019","volume":"97","author":"Rong","year":"2021","journal-title":"Neurology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1001\/jama.2019.22360","article-title":"Diagnosis and Treatment of Parkinson Disease: A Review","volume":"323","author":"Armstrong","year":"2020","journal-title":"JAMA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"155S","DOI":"10.1592\/phco.27.12part2.155S","article-title":"Overview of Parkinson\u2019s Disease","volume":"27","author":"Lew","year":"2007","journal-title":"Pharmacother. J. Hum. Pharmacol. Drug Ther."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Vacchi, E., Burrello, J., Burrello, A., Bolis, S., Monticone, S., Barile, L., Kaelin-Lang, A., and Melli, G. (2021). Profiling Inflammatory Extracellular Vesicles in Plasma and Cerebrospinal Fluid: An Optimized Diagnostic Model for Parkinson\u2019s Disease. Biomedicines, 9.","DOI":"10.3390\/biomedicines9030230"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1016\/S0140-6736(14)61393-3","article-title":"Parkinson\u2019s Disease","volume":"386","author":"Kalia","year":"2015","journal-title":"Lancet"},{"key":"ref_8","first-page":"1590465","article-title":"Microarray Analysis of the Molecular Mechanism Involved in Parkinson\u2019s Disease","volume":"2018","author":"Tan","year":"2018","journal-title":"Parkinsons Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/s41531-024-00636-y","article-title":"Early-Stage Idiopathic Parkinson\u2019s Disease Is Associated with Reduced Circular RNA Expression","volume":"10","author":"Whittle","year":"2024","journal-title":"npj Parkinsons Dis."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Diao, H., Li, X., Hu, S., and Liu, Y. (2012). Gene Expression Profiling Combined with Bioinformatics Analysis Identify Biomarkers for Parkinson Disease. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0052319"},{"key":"ref_11","first-page":"6755569","article-title":"Identification of Hub Genes and Potential Molecular Pathogenesis in Substantia Nigra in Parkinson\u2019s Disease via Bioinformatics Analysis","volume":"2023","author":"Zhou","year":"2023","journal-title":"Parkinsons Dis."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Xin, G., Niu, J., Tian, Q., Fu, Y., Chen, L., Yi, T., Tian, K., Sun, X., Wang, N., and Wang, J. (2023). Identification of Potential Immune-Related Hub Genes in Parkinson\u2019s Disease Based on Machine Learning and Development and Validation of a Diagnostic Classification Model. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0294984"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Su, L., Wang, C., Zheng, C., Wei, H., and Song, X. (2018). A Meta-Analysis of Public Microarray Data Identifies Biological Regulatory Networks in Parkinson\u2019s Disease. BMC Med. Genom., 11.","DOI":"10.1186\/s12920-018-0357-7"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.gene.2019.02.026","article-title":"Construction of Parkinson\u2019s Disease Marker-Based Weighted Protein-Protein Interaction Network for Prioritization of Co-Expressed Genes","volume":"697","author":"George","year":"2019","journal-title":"Gene"},{"key":"ref_15","unstructured":"Javali, S.B., Gudaganavar, N.V., and Raj, S.M. (2011). Effect of Varying Sample Size in Estimation of Coefficients of Internal Consistency. WEbmed Cent. Biostat., 2."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"103993","DOI":"10.1016\/j.mcn.2025.103993","article-title":"Identifying Potential Genes Driving Ferroptosis in the Substantia Nigra and Dopaminergic Neurons in Parkinson\u2019s Disease","volume":"132","author":"Chakrabarti","year":"2025","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Li, Y., Jia, W., Chen, C., Chen, C., Chen, J., Yang, X., and Liu, P. (2025). Identification of Biomarkers Associated with Inflammatory Response in Parkinson\u2019s Disease by Bioinformatics and Machine Learning. PLoS ONE, 20.","DOI":"10.1371\/journal.pone.0320257"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"619","DOI":"10.3233\/JIN-180091","article-title":"Bioinformatic Analysis for the Identification of Key Candidate Genes and Pathways in the Substantia Nigra in Parkinson\u2019s Disease","volume":"17","author":"Liu","year":"2018","journal-title":"J. Integr. Neurosci."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Huang, J., Li, B., Wei, H., Li, C., Liu, C., Mi, H., and Chen, S. (2024). Integrative Analysis of Gene Expression Profiles of Substantia Nigra Identifies Potential Diagnosis Biomarkers in Parkinson\u2019s Disease. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-52276-0"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"134950","DOI":"10.1016\/j.neulet.2020.134950","article-title":"Weighted Gene Co-Expression Network Analysis Reveals Specific Modules and Biomarkers in Parkinson\u2019s Disease","volume":"728","author":"Jin","year":"2020","journal-title":"Neurosci. Lett."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Chen, L., Wang, Y., Huang, J., Hu, B., and Huang, W. (2022). Identification of Immune-Related Hub Genes in Parkinson\u2019s Disease. Front. Genet., 13.","DOI":"10.3389\/fgene.2022.914645"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"D1102","DOI":"10.1093\/nar\/gky1033","article-title":"PubChem 2019 Update: Improved Access to Chemical Data","volume":"47","author":"Kim","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1093\/biostatistics\/4.2.249","article-title":"Exploration, Normalization, and Summaries of High Density Oligonucleotide Array Probe Level Data","volume":"4","author":"Irizarry","year":"2003","journal-title":"Biostatistics"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"Limma Powers Differential Expression Analyses for RNA-Sequencing and Microarray Studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic. Acids. Res."},{"key":"ref_25","first-page":"i38","article-title":"Kernel Methods for Predicting Protein-Protein Interactions","volume":"2","author":"Noble","year":"2005","journal-title":"Bioinformatics"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Mahmud, S., Ajadee, A., Sarker, A., Ahmmed, R., Noor, T., Pappu, M.A.A., Islam, M.S., and Mollah, M.N.H. (2025). Exploring Common Genomic Biomarkers to Disclose Common Drugs for the Treatment of Colorectal Cancer and Hepatocellular Carcinoma with Type-2 Diabetes through Transcriptomics Analysis. PLoS ONE, 20.","DOI":"10.1371\/journal.pone.0319028"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"D607","DOI":"10.1093\/nar\/gky1131","article-title":"STRING V11: Protein-Protein Association Networks with Increased Coverage, Supporting Functional Discovery in Genome-Wide Experimental Datasets","volume":"47","author":"Szklarczyk","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: A Software Environment for Integrated Models of Biomolecular Interaction Networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Lesnick, T.G., Papapetropoulos, S., Mash, D.C., Ffrench-Mullen, J., Shehadeh, L., de Andrade, M., Henley, J.R., Rocca, W.A., Ahlskog, J.E., and Maraganore, D.M. (2007). A Genomic Pathway Approach to a Complex Disease: Axon Guidance and Parkinson Disease. PLoS Genet., 3.","DOI":"10.1371\/journal.pgen.0030098"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Pappu, M.A.A., Alamin, M., Sultana, M.H., Azad, A.K.M., Auwul, M.R., Mahmud, S., Ajadee, A., Sarker, A., Alyami, S.A., and Mollah, M.N.H. (2025). Single Nucleus RNA Sequencing Profile Analysis to Reveal Cell Type Specific Common Molecular Drivers of Parkinson\u2019s Disease and Therapeutic Agents. Sci. Rep., 15.","DOI":"10.1038\/s41598-025-09417-w"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Ahmed, M.F., Al Noman, M., Ahmed, M.F., Latif, M.A., Pappu, M.A.A., Islam, M.S., Hossain, M.S., Hossen, M.B., Faysal, M.F., and Hasan, M.M. (2025). In-Silico Discovery of Pediatric Acute-Myeloid-Leukemia (PAML) Causing Druggable Molecular Signatures Highlighting Their Pathogenetic Processes and Therapeutic Agents through Single-Cell RNA-Seq Profile Analysis. PLoS ONE, 20.","DOI":"10.1371\/journal.pone.0335410"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"W90","DOI":"10.1093\/nar\/gkw377","article-title":"Enrichr: A Comprehensive Gene Set Enrichment Analysis Web Server 2016 Update","volume":"44","author":"Kuleshov","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_33","first-page":"D845","article-title":"The DisGeNET Knowledge Platform for Disease Genomics: 2019 Update","volume":"48","author":"Ronzano","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_34","first-page":"D87","article-title":"JASPAR 2020: Update of the Open-Access Database of Transcription Factor Binding Profiles","volume":"48","author":"Fornes","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1038\/nprot.2015.052","article-title":"NetworkAnalyst for Statistical, Visual and Network-Based Meta-Analysis of Gene Expression Data","volume":"10","author":"Xia","year":"2015","journal-title":"Nat. Protoc."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1261\/rna.2239606","article-title":"TarBase: A Comprehensive Database of Experimentally Supported Animal MicroRNA Targets","volume":"12","author":"Sethupathy","year":"2006","journal-title":"Rna"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"W783","DOI":"10.1093\/nar\/gki470","article-title":"GoPubMed: Exploring PubMed with the Gene Ontology","volume":"33","author":"Doms","year":"2005","journal-title":"Nucleic Acids Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"D480","DOI":"10.1093\/nar\/gkm882","article-title":"KEGG for Linking Genomes to Life and the Environment","volume":"36","author":"Kanehisa","year":"2008","journal-title":"Nucleic Acids Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene Set Enrichment Analysis: A Knowledge-Based Approach for Interpreting Genome-Wide Expression Profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"13767","DOI":"10.1080\/21655979.2022.2084253","article-title":"Based on Network Pharmacology and in Vitro Experiments to Prove the Effective Inhibition of Myocardial Fibrosis by Buyang Huanwu Decoction","volume":"13","author":"Wang","year":"2022","journal-title":"Bioengineered"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The Protein Data Bank","volume":"28","author":"Berman","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"D439","DOI":"10.1093\/nar\/gkab1061","article-title":"AlphaFold Protein Structure Database: Massively Expanding the Structural Coverage of Protein-Sequence Space with High-Accuracy Models","volume":"50","author":"Varadi","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3381","DOI":"10.1093\/nar\/gkg520","article-title":"SWISS-MODEL: An Automated Protein Homology-Modeling Server","volume":"31","author":"Schwede","year":"2003","journal-title":"Nucleic Acids Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"22","DOI":"10.24198\/ijcb.v2i1.46322","article-title":"Molecular Interaction Analysis and Visualization of Protein-Ligand Docking Using Biovia Discovery Studio Visualizer","volume":"2","author":"Baroroh","year":"2023","journal-title":"Indones. J. Comput. Biol. (IJCB)"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the Speed and Accuracy of Docking with a New Scoring Function, Efficient Optimization, and Multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Jayaram, B., Singh, T., Mukherjee, G., Mathur, A., Shekhar, S., and Shekhar, V. (2012). Sanjeevini: A Freely Accessible Web-Server for Target Directed Lead Molecule Discovery. BMC Bioinform., 13.","DOI":"10.1186\/1471-2105-13-S17-S7"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Daina, A., Michielin, O., and Zoete, V. (2017). SwissADME: A Free Web Tool to Evaluate Pharmacokinetics, Drug-Likeness and Medicinal Chemistry Friendliness of Small Molecules. Sci. Rep., 7.","DOI":"10.1038\/srep42717"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"4066","DOI":"10.1021\/acs.jmedchem.5b00104","article-title":"PkCSM: Predicting Small-Molecule Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures","volume":"58","author":"Pires","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1002\/prot.10104","article-title":"Increasing the Precision of Comparative Models with YASARA NOVA\u2014A Self-Parameterizing Force Field","volume":"47","author":"Krieger","year":"2002","journal-title":"Proteins Struct. Funct. Bioinform."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1668","DOI":"10.1002\/jcc.20290","article-title":"The Amber Biomolecular Simulation Programs","volume":"26","author":"Case","year":"2005","journal-title":"J. Comput. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1002\/jcc.23899","article-title":"New Ways to Boost Molecular Dynamics Simulations","volume":"36","author":"Krieger","year":"2015","journal-title":"J. Comput. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/j.jmgm.2006.02.009","article-title":"Fast Empirical PKa Prediction by Ewald Summation","volume":"25","author":"Krieger","year":"2006","journal-title":"J. Mol. Graph. Model"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3684","DOI":"10.1063\/1.448118","article-title":"Molecular Dynamics with Coupling to an External Bath","volume":"81","author":"Berendsen","year":"1984","journal-title":"J. Chem. Phys."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.jmgm.2018.04.014","article-title":"Structural Dynamics and Quantum Mechanical Aspects of Shikonin Derivatives as CREBBP Bromodomain Inhibitors","volume":"83","author":"Mitra","year":"2018","journal-title":"J. Mol. Graph. Model"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"102744","DOI":"10.1039\/C6RA21927F","article-title":"Computational Investigation of Curcumin, a Natural Polyphenol That Inhibits the Destabilization and the Aggregation of Human SOD1 Mutant (Ala4Val)","volume":"6","author":"Srinivasan","year":"2016","journal-title":"RSC Adv."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"D561","DOI":"10.1093\/nar\/gkq973","article-title":"The STRING Database in 2011: Functional Interaction Networks of Proteins, Globally Integrated and Scored","volume":"39","author":"Szklarczyk","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1089\/cmb.2019.0323","article-title":"Analysis of the Physicochemical Properties of Acaricides Based on Lipinski\u2019s Rule of Five","volume":"27","author":"Chen","year":"2020","journal-title":"J. Comput. Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.nbd.2009.07.028","article-title":"Approaches to Transport Therapeutic Drugs across the Blood\u2013Brain Barrier to Treat Brain Diseases","volume":"37","author":"Gabathuler","year":"2010","journal-title":"Neurobiol. Dis."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Wong, A.D., Ye, M., Levy, A.F., Rothstein, J.D., Bergles, D.E., and Searson, P.C. (2013). The Blood-Brain Barrier: An Engineering Perspective. Front. Neuroeng., 6.","DOI":"10.3389\/fneng.2013.00007"},{"key":"ref_60","unstructured":"Batista, P., and Pereira, A. (2016). Impact and Prevention of Neurodegenerative Diseases in Society: Alzheimer and Parkinson. Neurodegenerative Diseases, SM Group Open Access eBooks."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"222","DOI":"10.20517\/2347-8659.2020.58","article-title":"A Review on Parkinson\u2019s Disease Treatment","volume":"8","author":"Lee","year":"2021","journal-title":"Neuroimmunol. Neuroinflamm."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/j.molmed.2006.09.007","article-title":"Understanding the Molecular Causes of Parkinson\u2019s Disease","volume":"12","author":"Gandhi","year":"2006","journal-title":"Trends Mol. Med."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.neulet.2018.06.011","article-title":"GAPDH Rs1136666 SNP Indicates a High Risk of Parkinson\u2019s Disease","volume":"685","author":"Ping","year":"2018","journal-title":"Neurosci. Lett."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1111\/j.1460-9568.2005.03870.x","article-title":"Pro-apoptotic Protein Glyceraldehyde-3-phosphate Dehydrogenase Promotes the Formation of Lewy Body-like Inclusions","volume":"21","author":"Tsuchiya","year":"2005","journal-title":"Eur. J. Neurosci."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Liu, L., Xiong, N., Zhang, P., Chen, C., Huang, J., Zhang, G., Xu, X., Shen, Y., Lin, Z., and Wang, T. (2015). Genetic Variants in GAPDH Confer Susceptibility to Sporadic Parkinson\u2019s Disease in a Chinese Han Population. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0135425"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Erekat, N.S. (2018). Apoptosis and Its Role in Parkinson\u2019s Disease. Exon. Publ., 65\u201382.","DOI":"10.15586\/codonpublications.parkinsonsdisease.2018.ch4"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Primiani, C.T., Ryan, V.H., Rao, J.S., Cam, M.C., Ahn, K., Modi, H.R., and Rapoport, S.I. (2014). Coordinated Gene Expression of Neuroinflammatory and Cell Signaling Markers in Dorsolateral Prefrontal Cortex during Human Brain Development and Aging. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0110972"},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Kaltschmidt, B., Helweg, L.P., Greiner, J.F.W., and Kaltschmidt, C. (2022). NF-\u039aB in Neurodegenerative Diseases: Recent Evidence from Human Genetics. Front. Mol. Neurosci., 15.","DOI":"10.3389\/fnmol.2022.954541"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Santos-Lobato, B.L., Vidal, A.F., and Ribeiro-dos-Santos, \u00c2. (2021). Regulatory MiRNA\u2013MRNA Networks in Parkinson\u2019s Disease. Cells, 10.","DOI":"10.3390\/cells10061410"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Findeiss, E., Schwarz, S.C., Evsyukov, V., R\u00f6sler, T.W., H\u00f6llerhage, M., Chakroun, T., Nyk\u00e4nen, N.P., Shen, Y., Wurst, W., and Kohl, M. (2021). Comprehensive MiRNome-Wide Profiling in a Neuronal Cell Model of Synucleinopathy Implies Involvement of Cell Cycle Genes. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.561086"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1007\/s13577-019-00295-9","article-title":"CCND1 Silencing Suppresses Liver Cancer Stem Cell Differentiation through Inhibiting Autophagy","volume":"33","author":"Zhang","year":"2020","journal-title":"Hum. Cell"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Ogino, M., Ichimura, M., Nakano, N., Minami, A., Kitagishi, Y., and Matsuda, S. (2016). Roles of PTEN with DNA Repair in Parkinson\u2019s Disease. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17060954"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1089\/ars.2008.2263","article-title":"Oxidative Stress and Autophagy in the Regulation of Lysosome-Dependent Neuron Death","volume":"11","author":"Pivtoraiko","year":"2009","journal-title":"Antioxid Redox Signal"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1007\/s10072-014-1651-6","article-title":"APOE and LRPAP1 Gene Polymorphism and Risk of Parkinson\u2019s Disease","volume":"35","author":"Singh","year":"2014","journal-title":"Neurol. Sci."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1007\/s12031-017-0942-9","article-title":"Role of Apolipoproteins and \u03b1-Synuclein in Parkinson\u2019s Disease","volume":"62","author":"Emamzadeh","year":"2017","journal-title":"J. Mol. Neurosci."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"203","DOI":"10.3892\/mmr.2023.13090","article-title":"Serum-derived Exosomal Hsa-let-7b-5p as a Biomarker for Predicting the Severity of Coronary Stenosis in Patients with Coronary Heart Disease and Hyperglycemia","volume":"28","author":"Han","year":"2023","journal-title":"Mol. Med. Rep."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"8595","DOI":"10.18632\/aging.204359","article-title":"ESR1 Dysfunction Triggers Neuroinflammation as a Critical Upstream Causative Factor of the Alzheimer\u2019s Disease Process","volume":"14","author":"Liu","year":"2022","journal-title":"Aging"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1002\/jnr.24331","article-title":"Neuroinflammation and Blood\u2013Brain Barrier Disruption Following Traumatic Brain Injury: Pathophysiology and Potential Therapeutic Targets","volume":"98","author":"Sulhan","year":"2020","journal-title":"J. Neurosci. Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"4183","DOI":"10.1002\/ptr.7552","article-title":"Nootkatone Alleviates Rotenone-induced Parkinson\u2019s Disease Symptoms through Activation of the PI3K\/Akt Signaling Pathway","volume":"36","author":"Yao","year":"2022","journal-title":"Phytother. Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"e34113","DOI":"10.1016\/j.heliyon.2024.e34113","article-title":"Research on the Mechanism of Ursolic Acid for Treating Parkinson\u2019s Disease by Network Pharmacology and Experimental Verification","volume":"10","author":"Sun","year":"2024","journal-title":"Heliyon"},{"key":"ref_81","first-page":"4318416","article-title":"Genetic Variants in SNCA and the Risk of Sporadic Parkinson\u2019s Disease and Clinical Outcomes: A Review","volume":"2017","author":"Silva","year":"2017","journal-title":"Parkinsons Dis."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1038\/s41531-021-00196-5","article-title":"A Systematic Review of Associations between Common SNCA Variants and Clinical Heterogeneity in Parkinson\u2019s Disease","volume":"7","author":"Pedersen","year":"2021","journal-title":"npj Parkinsons Dis."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1002\/ana.24664","article-title":"\u03b1-Synuclein Genetic Variability: A Biomarker for Dementia in Parkinson\u2019s Disease","volume":"79","author":"Parkkinen","year":"2016","journal-title":"Ann. Neurol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1002\/ana.21192","article-title":"Tau and A-synuclein in Susceptibility to, and Dementia in, Parkinson\u2019s Disease","volume":"62","author":"Goris","year":"2007","journal-title":"Ann. Neurol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1093\/brain\/awad388","article-title":"Nigrostriatal Tau Pathology in Parkinsonism and Parkinson\u2019s Disease","volume":"147","author":"Chu","year":"2024","journal-title":"Brain"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"2105","DOI":"10.1074\/jbc.M410468200","article-title":"Mechanistic and Structural Analysis of a Family 31 \u03b1-Glycosidase and Its Glycosyl-Enzyme Intermediate","volume":"280","author":"Lovering","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"e00470","DOI":"10.1002\/prp2.470","article-title":"Pharmacokinetics and Pharmacodynamics of a Single Dose Nilotinib in Individuals with Parkinson\u2019s Disease","volume":"7","author":"Pagan","year":"2019","journal-title":"Pharmacol. Res. Perspect."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1056\/NEJM197612162952504","article-title":"Treatment of Parkinson\u2019s Disease with Bromocriptine","volume":"295","author":"Lieberman","year":"1976","journal-title":"New Engl. J. Med."},{"key":"ref_89","first-page":"CD002258","article-title":"Bromocriptine versus Levodopa in Early Parkinson\u2019s Disease","volume":"2009","author":"Ramaker","year":"2007","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s12993-019-0160-4","article-title":"Neuroprotective Effects of Withania Somnifera in BPA Induced-Cognitive Dysfunction and Oxidative Stress in Mice","volume":"15","author":"Birla","year":"2019","journal-title":"Behav. Brain Funct."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"112769","DOI":"10.1016\/j.jep.2020.112769","article-title":"Neurodegenerative Diseases and Withania Somnifera (L.): An Update","volume":"256","author":"Dar","year":"2020","journal-title":"J. Ethnopharmacol."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Lin, M.W., Lin, C.C., Chen, Y.H., Yang, H.B., and Hung, S.Y. (2019). Celastrol Inhibits Dopaminergic Neuronal Death of Parkinson\u2019s Disease through Activating Mitophagy. Antioxidants, 9.","DOI":"10.3390\/antiox9010037"},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Bai, X., Fu, R.J., Zhang, S., Yue, S.J., Chen, Y.Y., Xu, D.Q., and Tang, Y.P. (2021). Potential Medicinal Value of Celastrol and Its Synthesized Analogues for Central Nervous System Diseases. Biomed. Pharmacother., 139.","DOI":"10.1016\/j.biopha.2021.111551"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1111\/j.1749-6632.2002.tb04856.x","article-title":"Responses to Donepezil in Alzheimer\u2019s Disease and Parkinson\u2019s Disease","volume":"977","author":"Mori","year":"2002","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1230","DOI":"10.1002\/mds.25098","article-title":"Donepezil in Parkinson\u2019s Disease Dementia: A Randomized, Double-blind Efficacy and Safety Study","volume":"27","author":"Dubois","year":"2012","journal-title":"Mov. Disord."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1517\/14728214.11.3.403","article-title":"Emerging drugs for Parkinson\u2019s disease","volume":"11","author":"Morgan","year":"2006","journal-title":"Expert Opin. Emerg. Drugs"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1097\/NRL.0b013e318158e47d","article-title":"Medications for Parkinson\u2019s disease","volume":"13","author":"Whitney","year":"2007","journal-title":"Neurologist"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.1001\/jama.1969.03160070046011","article-title":"Amantadine in the treatment of Parkinson\u2019s disease","volume":"208","author":"Schwab","year":"1969","journal-title":"JAMA"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"107547","DOI":"10.1016\/j.jmgm.2020.107547","article-title":"Identification of potential natural neuroprotective molecules for Parkinson\u2019s disease by using chemoinformatics and molecular docking","volume":"97","year":"2020","journal-title":"J. Mol. Graph. Model."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1517\/17425255.2013.789018","article-title":"Anti-Parkinson\u2019s disease drugs and pharmacogenetic considerations","volume":"9","year":"2013","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1016\/S0025-7125(05)70118-8","article-title":"Novel drugs for Parkinson\u2019s disease","volume":"83","author":"Hubble","year":"1999","journal-title":"Med. Clin. N. Am."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1007\/s00702-016-1629-z","article-title":"Muscarinic receptor binding changes in postmortem Parkinson\u2019s disease","volume":"124","author":"McOmish","year":"2017","journal-title":"J. Neural Transm."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"3069","DOI":"10.1093\/bioinformatics\/btv313","article-title":"DSigDB: Drug signatures database for gene set analysis","volume":"31","author":"Yoo","year":"2015","journal-title":"Bioinformatics"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1007\/s40263-018-0548-y","article-title":"Drug repurposing in Parkinson\u2019s disease","volume":"32","author":"Athauda","year":"2018","journal-title":"CNS Drugs"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1038\/nmeth.2689","article-title":"DGIdb: Mining the druggable genome","volume":"10","author":"Griffith","year":"2013","journal-title":"Nat. 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