Targeting neurodegenerative disease-associated protein aggregation with proximity-inducing modalities.

Abstract

Neurodegenerative diseases (NDDs) are characterized by progressive neuronal dysfunction and anatomical changes caused by neuron loss and gliosis, ultimately leading to severe declines in brain function. While these disorders arise from a variety of pathological mechanisms, a common molecular feature is the accumulation of misfolded proteins, which occurs both inside and outside neurons. For example, Alzheimer's disease (AD) is defined by extracellular β-amyloid plaques and intracellular tau neurofibrillary tangles. These pathological protein aggregates are often resistant to traditional small molecule drugs. Recent advances in proximity-inducing chimeras such as proteolysis-targeting chimeras (PROTACs), lysosome-targeting chimeras (LYTACs), autophagy-targeted chimeras (AUTOTACs), dephosphorylation-targeting chimeras (DEPTACs) and ribonuclease-targeting chimeras (RIBOTACs) offer promising strategies to eliminate pathological proteins or mRNAs through intracellular degradation pathways. These innovative approaches open avenues for developing new therapies for NDDs. In this review we summarize the regulatory mechanisms of protein aggregation, highlight the advancements in proximity-inducing modalities for NDDs, and discuss the current challenges and future directions in therapeutic development.