The molecular and genetic view of tauopathies: From structural polymorphism to systemic neurodegeneration

Abstract

Tauopathies constitute a broad group of clinically heterogeneous neurodegenerative disorders, including Alzheimer’s disease, progressive supranuclear palsy, and Pick’s disease, characterized by abnormal metabolism, misfolding, and intracellular aggregation of the microtubule-associated protein tau. These diseases are defined by disruptions in alternative splicing of the tau protein, toxic post-translational modifications such as hyperphosphorylation and acetylation, and the “prion-like” spread of pathological tau seeds across anatomically connected regions. Recent cryogenic electron microscopy studies have demonstrated that each tauopathy has a unique filament-folding structure, elucidating the molecular basis of phenotypic variation among diseases. The aim of this review is to provide a holistic perspective by synthesizing recent developments in the molecular and genetic architecture of tauopathies, particularly newly discovered genetic risk loci and cellular proteostasis mechanisms. In this context, detailing the process from the physiological functions of the tau protein to its pathological transformation aims to analytically evaluate the diagnostic value of fluid biomarkers and current data on next-generation clinical-stage therapeutic strategies, such as monoclonal antibodies and antisense oligonucleotides.