Protein Aggregation and Proteostasis Failure in Neurodegenerative Diseases: Mechanisms, Structural Insights, and Therapeutic Strategies

Protein aggregation is a defining pathological hallmark of major neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and tauopathies. These disorders share a convergent failure of proteostasis—the integrated network that regulates protein synthesis, folding, trafficking, and clearance—rather than isolated, disease-specific anomalies. Neurons, as long-lived post-mitotic cells, are particularly vulnerable to proteostasis collapse, which promotes accumulation of misfolded proteins such as amyloid-β, α-synuclein, tau, and TDP-43. Aggregates exhibit structural polymorphism, prion-like propagation, and strain-specific conformations that dictate regional vulnerability and clinical heterogeneity. Mechanistically, clearance pathways—including the ubiquitin–proteasome system, autophagy–lysosomal axis, endosomal–lysosomal trafficking, and molecular chaperones—operate in a highly coordinated manner; their dysfunction accelerates aggregation and neurotoxicity. Emerging evidence implicates liquid-liquid phase separation as a precursor to amyloid formation, while post-translational modifications such as phosphorylation, ubiquitination, and truncation modulate aggregation kinetics and pathogenicity. Aging further exacerbates proteostasis failure through impaired autophagic flux, lysosomal dysfunction, and glymphatic clearance decline, amplifying aggregate burden and prion-like dissemination. Despite extensive development of aggregation inhibitors, immunotherapies, and proteostasis enhancers, clinical translation remains limited due to poor blood–brain barrier penetration, off-target effects, and incomplete understanding of intermediate toxic species. Future strategies should integrate structural biology, seed amplification assays, and systems-level approaches to target early aggregation events, reinforce clearance pathways, and modulate neuroinflammation. This review synthesizes mechanistic insights, structural data, and therapeutic advances, emphasizing the complexity of protein aggregation as a dynamic, multifactorial process in neurodegeneration.