Exploring Protein Misfolding and Aggregate Pathology in Neurodegenerative Diseases: From Molecular Mechanisms to Clinical Interventions

Neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease are characterized by progressive neuronal loss, driven mainly by the misfolding, aggregation, and accumulation of each disease’s specific proteins. These pathogenic aggregates, including tau, α-synuclein, TDP-43, and huntingtin, disrupt cellular proteostasis and initiate cascades of neuroinflammation, oxidative stress, mitochondrial dysfunction, and synaptic failure. While protein aggregation has been a long-recognized hallmark of these disorders, growing evidence points towards a more complex interplay of initial molecular pathways with defects in RNA processing, stress granule pathology, and cell-type-specific vulnerability. Notably, such events may manifest differentially with respect to sex and are further modulated by age-related loss of the protein quality control processes like the ubiquitin–proteasome pathway, autophagy–lysosome pathway, and molecular chaperones. This review synthesizes current insights into the structural and functional dynamics of protein aggregation and its significance for neuronal well-being. It highlights the role of post-translational modifications, prion-like transmission, and aggregation kinetics in the regulation of toxicity. The review further discusses promising therapeutic strategies centered on restoring proteostasis, including small molecules that inhibit aggregation, protein clearance pathway enhancers, immunotherapy, antioxidant therapy, and diagnostic prospects such as the identification of reliable molecular signatures in bodily fluids that can reflect pathological changes even before clinical symptoms emerge. Advancements in single-cell transcriptomics and multi-omics platforms, which are changing our understanding of disease onset and progression and opening avenues for precision medicine and personalized treatments, were also discussed. Ultimately, deciphering the molecular logic that distinguishes physiological from pathological protein assemblies and understanding how cellular systems fail to adapt under stress will be key to the development of effective, disease-modifying therapies for these debilitating disorders.