CHARACTERIZATION, INVESTIGATION AND CLEARANCE MECHANISM OF NEUROTOXIC PROTEINS IN ALZHEIMER’S AND PARKINSON’S DISEASE

Abstract

The abnormal accumulations of altered proteins are common pathological hallmarks of various neurodegenerative disorders (NDDs) such as Alzheimer‟s and Parkinson‟s disease, the leading cause of disability and death worldwide. Originally, AD and PD are famous for being two distinct NDDs with primarily memory and motor dysfunctions respectively. However, their pathologies share some overlapping proteinopathy along with the standard amyloid-beta (Aβ) plaques, tau associated neurofibrillary tangles, and α-synuclein containing lewy bodies. Recent discoveries have identified amyloid-beta precursor protein (AβPP) central to the pathogenesis of both diseases, including Aβ formation in AD and amyloid intracellular domain (AICD) associated mitochondrial regulation and neurotoxicity in PD. Here, ubiquitination plays an eminent role in the regulation of cellular proteomic balance and triggers distinct cellular responses based on the poly-ubiquitination patterns on their substrates. Therefore, the proteasomal regulation of AβPP is crucial for cell to overcome the amyloid burden and consequent AICD associated pathologies to maintain its healthy state. Moreover, the molecular diagnoses of the UPS components (including E1s, E2s and E3s) and their mechanism for abnormal protein clearance is decisive for developing the promising therapeutic modalities for better public health. Herein, we reviewed the dynamics of UPS machinery for the clearance of toxic metabolites in various neurodegenerative disorders and found that target specific ubiquitin E3 ligases, and their precise mechanism of lysine selectivity and ubiquitination are still rudimentary for most of the markers. Therefore, main goal of this PhD research is to investigate the ubiquitination mechanism of AβPP and explore the potential ubiquitination sites responsible for AβPP processing and degradation to arrest Aβ formation and consequent pathologies. In addition, we identified the crucial factors for lysine selection during AβPP ubiquitination, including the conserved neighboring residues and secondary structural conformations in protein. Further, we studied the impact of lysine residues on AβPP stability, and their plausible role in non-covalent interactions for ubiquitin-positioning and ubiquitin-AβPP conjugation during ubiquitination and other functions. Furthermore, we elucidated the interaction pattern of AβPP with AD and PD-related proteins and reported the commonly interacting factors among Aβ, Tau and α- ii

synuclein for governing AD and PD pathogenesis. Moreover, we identified the key ubiquitination enzymes and their interactional network to deduce the regulation of Aβ, AβPP, Tau and α-synuclein ubiquitination. Additionally, we have also identified the aggregation prone regions in Aβ, Tau and α-synuclein that revealed the potential lysine residues for stabilizing the aggregates. These findings reveal novel regulatory mechanisms that would help us to device promising therapies to improve the mental, emotional, social and economic lives of the patients.