Liquid–liquid phase separation of Tau and α-synuclein: a new target for treating comorbidity in neurodegeneration

Abstract

Alzheimer’s and Parkinson’s diseases are the most common neurodegenerative disorders, causing significant disability and mortality worldwide. Though traditionally classified as Tau and α-synuclein-related disorders, respectively, there is growing evidence of clinical overlap between dementia and Parkinsonism, with comorbidity worsening cognitive impairment and prognosis. Emerging research on liquid–liquid phase separation (LLPS) offers promising insights into novel treatments of these proteinopathies by targeting the phase behavior of the disease-associated proteins. Thus, manipulating condensates has become a focus for developing new therapeutic compounds, termed condensate-modifying drugs (c-mods), by which historically considered undruggable proteins can be targeted. This review offers an overview of bioactive molecules that act as modifiers of Tau and α-synuclein condensates through various mechanisms. The goal is to lay the groundwork for discovering new therapeutic approaches to prevent harmful protein aggregation and treat comorbidity in tau and synucleinopathies.