{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T11:10:01Z","timestamp":1790334601247,"version":"4.1.0"},"reference-count":192,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T00:00:00Z","timestamp":1790294400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:p>Tau dysregulation, particularly abnormal phosphorylation, is increasingly implicated in Parkinson\u2019s disease (PD) and in the pathogenic interaction between Tau and \u03b1-synuclein. This review proposes an integrated PD-focused workflow connecting phosphoproteomic discovery, structural modeling, computational drug discovery, and experimental validation. Phosphoproteomic analyses of post-mortem brain tissue, biofluids, and patient-derived dopaminergic neuronal models can identify candidate Tau phosphosignatures associated with vulnerable brain regions, \u03b1-synuclein pathology, genetic background, or clinical progression. Molecular dynamics simulations can then evaluate how these signatures alter Tau conformation, microtubule binding, aggregation-prone motifs, membrane association, and pathogenic protein interactions. The resulting structural information can guide ensemble docking, chemoinformatics, and artificial intelligence approaches to prioritize conformer-selective ligands and regulatory targets. Candidate biomarkers should subsequently be validated in independent and longitudinal PD cohorts, whereas therapeutic candidates require mechanistic and functional validation in PD-relevant experimental models before clinical translation. This iterative framework may help distinguish mechanistically relevant Tau phosphoconformers from nonspecific phosphorylation changes, support biomarker-based patient stratification, and focus therapeutic development on structurally defined pathological states. Because much of the available structural evidence derives from Alzheimer\u2019s disease and other tauopathies, direct validation in PD remains essential. By linking PD-derived and disease-relevant molecular evidence with atomistic mechanisms and therapeutic prioritization, this workflow may support biomarker-informed strategies aimed at restoring Tau homeostasis and disrupting pathogenic Tau\u2013\u03b1-synuclein interactions.<\/jats:p>","DOI":"10.3389\/fnagi.2026.1841131","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T10:39:28Z","timestamp":1790332768000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Tau protein in Parkinson\u2019s disease: advances in phosphoproteomics and molecular dynamics simulations"],"prefix":"10.3389","volume":"18","author":[{"given":"Jessica","family":"Ledesma-Aparicio","sequence":"first","affiliation":[{"name":"Laboratory of Regenerative Medicine, Department of Physiology, Faculty of Medicine, National Autonomous University of Mexico","place":["Mexico City, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis Alberto","family":"Caro-G\u00f3mez","sequence":"additional","affiliation":[{"name":"Laboratory of Regenerative Medicine, Department of Physiology, Faculty of Medicine, National Autonomous University of Mexico","place":["Mexico City, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco Javier","family":"Padilla-God\u00ednez","sequence":"additional","affiliation":[{"name":"Department of Mathematics and Physics, Western Institute of Technology and Higher Education","place":["San Pedro Tlaquepaque, Jalisco, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omar","family":"Hern\u00e1ndez-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Laboratory of Regenerative Medicine, Department of Physiology, Faculty of Medicine, National Autonomous University of Mexico","place":["Mexico City, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis O.","family":"Soto-Rojas","sequence":"additional","affiliation":[{"name":"Laboratory of Neuroscience, Aging and Neurodegeneration (LINEN), Medical Degree Program, Faculty of Higher Studies Iztacala, National Autonomous University of Mexico (UNAM)","place":["Tlalnepantla, State of Mexico, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Pablo","family":"Reyes-Grajeda","sequence":"additional","affiliation":[{"name":"Protein Structure Laboratory, National Institute of Genomic Medicine (INMEGEN)","place":["Mexico City, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oscar","family":"Arias-Carri\u00f3n","sequence":"additional","affiliation":[{"name":"Division of Clinical Neurosciences, National Institute of Rehabilitation","place":["Mexico City, Mexico"]},{"name":"Tecnol\u00f3gico de Monterrey, School of Medicine and Health Sciences","place":["Mexico City, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcela","family":"Palomero-Rivero","sequence":"additional","affiliation":[{"name":"Department of Cognitive Neuroscience, Division of Neurosciences, Institute of Cellular Physiology, National Autonomous University of Mexico","place":["Mexico City, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandt","family":"Bertrand","sequence":"additional","affiliation":[{"name":"Biological Membrane Physics Laboratory, Institute of Physical Sciences, National Autonomous University of Mexico","place":["Cuernavaca, Morelos, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Munoz-Garay","sequence":"additional","affiliation":[{"name":"Biological Membrane Physics Laboratory, Institute of Physical Sciences, National Autonomous University of Mexico","place":["Cuernavaca, Morelos, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Guerra-Crespo","sequence":"additional","affiliation":[{"name":"Laboratory of Regenerative Medicine, Department of Physiology, Faculty of Medicine, National Autonomous University of Mexico","place":["Mexico City, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,25]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1038\/labinvest.2014.156","article-title":"MALDI imaging mass spectrometry: current frontiers and perspectives in pathology research and practice","volume":"95","author":"Aichler","year":"2015","journal-title":"Lab. 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