Ubiquitin biology in neurodegenerative disorders: From impairment to therapeutic strategies

•UPS has implicated in learning and memory, drug addiction and brain homeostasis.•E3-ligase can both aggravate and ameliorate neuropathology based on their target protein.•Parkin, CHIP, TRAF-6, UBE3A, UBE2A, UBE2D, and UBE2K are common regulators of different NDDs.•Target specific UPS modulation can only alleviate the disease pathogenesis.•Allosteric modification of UPS is the key therapeutic approach against NDDs. The abnormal accumulation of neurotoxic proteins is the typical hallmark of various age-related neurodegenerative disorders (NDDs), including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Amyotrophic lateral sclerosis and Multiple sclerosis. The anomalous proteins, such as Aβ, Tau in Alzheimer’s disease and α-synuclein in Parkinson’s disease, perturb the neuronal physiology and cellular homeostasis in the brain thereby affecting the millions of human lives across the globe. Here, ubiquitin proteasome system (UPS) plays a decisive role in clearing the toxic metabolites in cells, where any aberrancy is widely reported to exaggerate the neurodegenerative pathologies. In spite of well-advancement in the ubiquitination research, their molecular markers and mechanisms for target-specific protein ubiquitination and clearance remained elusive. Therefore, this review substantiates the role of UPS in the brain signaling and neuronal physiology with their mechanistic role in the NDD’s specific pathogenic protein clearance. Moreover, current and future promising therapies are discussed to target UPS-mediated neurodegeneration for better public health.