Contemporary trends in targeted protein degradation for neurodegenerative diseases

Neurodegenerative diseases (NDs), including Alzheimer's, Huntington's, and Parkinson's disease, are associated with significant declines in cognitive function and mobility. The accumulation of misfolded proteins such as β-amyloid, tau, α-synuclein, and polyglutamates is a key factor in the progression of these conditions. Unfortunately, traditional small-molecule drugs face major obstacles in effectively targeting these proteins. In recent times, there has been a growing interest among researchers in the pharmaceutical field in utilizing small molecules to degrade proteins as a therapeutic strategy, specifically. This approach, also known as targeted protein degradation (TPD), has shown great potential and is gaining increasing attention. Particularly, two techniques - Proteolysis Targeting Chimeras (PROTACs) and Lysosome-Targeting Chimeras (LYTACs) - have emerged as highly promising methods for eliminating disease-associated proteins by leveraging the natural destruction processes within cells. Numerous novel TPD strategies, such as molecular glue, Antibody-based PROTAC (AbTAC), AUTOphagy-TArgeting Chimera (AUTOTAC), and bispecific aptamer chimera, are emerging alongside PROTAC and LYTAC. These cutting-edge technologies are expanding TPD's possibilities and bringing fresh insights into drug discovery. Here, we present a concise overview of the latest advancements in different TPD technologies. We delve into their potential applications in ND and strive to provide a comprehensive guide for biologists and chemists interested in exploring this rapidly evolving field.