Tau protein in Parkinson's disease: advances in phosphoproteomics and molecular dynamics simulations.

Abstract

Tau dysregulation, particularly abnormal phosphorylation, is increasingly implicated in Parkinson's disease (PD) and in the pathogenic interaction between Tau and α-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, α-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's 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-α-synuclein interactions.