The potential role and value of phosphorylated tau protein in the pathogenesis of Parkinson’s disease: research progress

Research on the pathological mechanisms of PD has long focused on the aggregation of α-synuclein, but the role of phosphorylated tau (p-tau) protein in the onset, progression, and conversion to Parkinson’s disease dementia has received increasing attention. Based on a systematic search of PubMed and Web of Science, this article reviews the physiological functions of tau protein and its neurotoxic effects after phosphorylation, and systematically summarizes the clinical and pathological evidence for p-tau at different clinical stages of PD (the prodromal stage characterized by rapid eye movement sleep behavior disorder, the clinical stage dominated by motor symptoms, and the advanced stage accompanied by dementia). Crucially, we explicitly distinguish correlational human neuropathological observations from causal inference: the cascade relationship between amyloid β (Aβ) and tau pathology described in Alzheimer’s disease (AD) is used only as an analogy, and the proposed “α-synuclein initiates, p-tau mediates toxicity” model for PD is presented as a hypothesis to be tested rather than as an established mechanism. By drawing on the cascade between Aβ and tau in AD, the potential timing and mechanisms of p-tau in the pathological process of PD are discussed. Furthermore, this article discusses new strategies for detecting p-tau through peripheral biomarkers such as skin biopsy to assist in the diagnosis and pathological staging of PD, while explicitly acknowledging that direct evidence for cutaneous p-tau in PD remains very limited and that current skin-biopsy data relate almost exclusively to α-synuclein; it then reviews the current status of p-tau pathology research in existing PD animal models, including the discrepancies between neurotoxin models and genuine human PD pathology, aiming to provide a theoretical basis for a comprehensive understanding of the complex pathological network of PD and the development of new therapeutic targets.