Molecular Mechanisms and Therapeutic Potential of Degron-Mediated Proteostasis Regulation in Neurodegenerative Diseases

Aberrant aggregation of specific proteins-such as amyloid beta, α-synuclein, tau, TDP-43, and PrPSc-is a hallmark anomaly in the brain micro-environment, leading to a cascade of pathological events including neuroinflammation, neuronal death, cognitive impairment, and memory loss. The dysregulation in cellular protein homeostasis promotes pathological protein aggregation and hastening disease progression. Degrons are short amino acid motifs within proteins that are recognized by E3 ubiquitin ligases, which target them for degradation via the ubiquitin-proteasome system or autophagy. Recent studies emphasize that alterations in degron sequences, changes after translation or structural modifications can hinder protein homeostasis, leading to their accumulation and contributing neural toxicity. This review integrates the mechanistic role of degron with their pathological relevance and therapeutic significance in neurodegenerative diseases includes Alzheimer's disease, Parkinson's disease, Sclerosis, frontotemporal dementia, and prion diseases and further investigates the translational potential of degron-targeting techniques, including emerging biotechnological startups developing degron-based therapeutic platforms.