2026 Volume 43 Issue 2 Pages 93-96
Many neurodegenerative disorders are characterized by the presence of abnormal protein aggregates within neurons. It has become increasingly evident that the aggregated proteins themselves, or molecular modifiers and degradation factors that are closely involved in their metabolism, correspond to the causative gene products or disease–susceptibility gene products in various hereditary neurodegenerative diseases. Through experimental validation using model cell systems and animal models based on this concept, it has now been concluded with a high degree of certainty that abnormal protein aggregation plays a critical role in disease pathogenesis (Nat Rev Mol Cell Biol 25:926, 2024).
Despite the widespread view that “abnormal protein aggregation” is directly linked to the etiology of neurodegenerative diseases, pharmacological agents that promote or facilitate human protein degradation systems―namely the autophagy–lysosome pathway (ALP) and the ubiquitin–proteasome system (UPS)―have not yet been translated into clinical practice. Clearance of this hurdle is expected to establish definitive evidence for the true contribution of protein aggregation to disease pathophysiology in humans.
In this review, owing to space limitations, we focus on Alzheimer disease (AD) and Parkinson disease (PD), which are highly prevalent neurodegenerative disorders, and provide a concise overview of their relationship with intracellular protein degradation systems. Based on this overview, we summarize the current landscape of ALP–related and UPS–related therapeutic agents. In particular, we highlight the remarkable recent advances in our understanding of the molecular mechanisms underlying selective ALP, and briefly discuss emerging drug discovery strategies targeting this pathway.
