Protein aggregate

Protein aggregates are insoluble assemblies of misfolded proteins that escape cellular quality control mechanisms like the ubiquitin-proteasome system and autophagy [3, 7]. These structures, often forming amyloid fibrils with a cross-beta sheet conformation, are central to the pathology of various proteinopathies [11, 15]. In neurodegenerative diseases such as Alzheimer's and Parkinson's, specific proteins like Amyloid-beta, Tau, and alpha-synuclein aggregate, leading to synaptic dysfunction, neuroinflammation, and neuronal death [1, 7, 13]. Therapeutic strategies focus on preventing the formation of these aggregates, stabilizing the native protein structure, or using monoclonal antibodies to facilitate their clearance from the brain [4, 5, 12]. For example, drugs like Lecanemab target Amyloid-beta aggregates to slow cognitive decline in Alzheimer's patients [16, 18]. Other approaches involve small molecules like Tafamidis that stabilize the native state of proteins to prevent the initial misfolding event [15]. Despite their promise, targeting protein aggregates remains challenging due to the difficulty of distinguishing toxic species from functional proteins [11, 15]. Additionally, safety concerns such as Amyloid-Related Imaging Abnormalities (ARIA) have been observed with certain anti-aggregate immunotherapies [16, 18]. The development of sensitive biomarkers, including PET imaging and fluid-based assays, is crucial for monitoring the efficacy of these treatments [1, 2, 10]. Overall, protein aggregates represent a critical but complex target class in the quest for disease-modifying therapies for chronic degenerative conditions [4, 7, 12].

Other names

Amyloid fibrilMisfolded protein assemblyProteotoxic aggregateInclusion bodyOligomerAmyloid plaqueNeurofibrillary tangleLewy bodyPrion

Drugs targeting protein aggregates primarily work through the inhibition of aggregate formation, stabilization of the native protein conformation to prevent misfolding, or the promotion of aggregate clearance via monoclonal antibodies that trigger microglial phagocytosis [4, 5, 15]. Some therapies also aim to degrade the precursor mRNA to reduce the overall protein burden, while others focus on disrupting pre-formed fibrils into non-toxic species [11, 12, 14].