MECHANISMS OF PROTEIN AGGREGATION IN NEURODEGENERATIVE DISEASES: CHEMICAL APPROACHES TO MODULATING PROTEIN MISFOLDING AND TOXICITY

Abstract

Neurodegenerative diseases including Alzheimer's and Parkinson's present with protein aggregation that causes dysfunctional neurons and results in impaired brain function. Modifying O-GlcNAcylation and increasing cellular processing of misfolded proteins represents an emerging therapeutic approach together with effective protein aggregation interruption. Research has shown that tau phosphorylation together with aggregation decreases when O-GlcNAc levels increase through O-GlcNAcase (OGA) inhibition which makes O-GlcNAc a promising new therapeutic approach for tauopathies. An important breakthrough for Alzheimer's disease treatment emerged with the development of RI-AG03 molecules which spread across multiple sites where tau proteins aggregate. RI-AG03 shows high efficacy in inhibiting tau aggregation according to preclinical studies therefore becoming the leading candidate therapy for Alzheimer's disease among available drugs that modify disease progression. Research developments confirm protein aggregation reduction as well as proteostasis optimization as foundational strategies for developing effective treatments against neurodegenerative diseases..