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

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.