Protein Misfolding & Neurodegenerative Diseases

Protein misfolding and neurodegenerative disease research examines abnormal protein conformations, aggregate formation, and neuronal injury. Neurodegenerative disorders show progressive neuronal loss and accumulation of misfolded or aggregated proteins. Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and prion diseases are linked to disease-associated protein aggregates, including amyloid-β, tau, α-synuclein, huntingtin, SOD1, and TDP-43. Proteostasis disruption, age-related decline in protein quality control, and failed protein clearance define the central experimental framework of this field^[1][2][3][4].
Mechanistically, molecular chaperones, the ubiquitin-proteasome system, chaperone-mediated autophagy, and macroautophagy maintain protein homeostasis. Misfolded proteins expose hydrophobic surfaces and can form toxic aggregates. Aggregation-prone substrates resistant to UPS or CMA degradation can enter the macroautophagy-lysosome pathway. Accumulation of misfolded proteins in the endoplasmic reticulum activates the unfolded protein response, and unresolved ER stress can shift UPR signaling toward cell death. Mitochondrial unfolded protein response, oxidative stress, mitochondrial dysfunction, neuroinflammation, and synaptic failure also contribute to disease progression^{[2][4][5][6][7]}.
Disease applications focus on Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, ALS, prion diseases, and spinocerebellar ataxia for mechanism studies, drug screening, and biomarker development. Experimental strategies include inhibiting aggregation, enhancing chaperone function, promoting UPS and autophagy-lysosome clearance, modulating UPR signaling, antioxidant therapy, and immunotherapy. Key gaps include incomplete definition of toxic aggregate species, complex prion-like transmission, cell-type-specific vulnerability, limited early diagnostic biomarkers, and difficult clinical translation. Future studies should combine single-cell omics, multi-omics, fluid molecular signatures, and protein clearance pathway modulation to support disease-modifying therapy development^{[1][2][3][5][7]}.