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A?, a risk factor for Parkinson???s pathogenesis: Mechanisms and prevention

Author(s): Mahesh Narayan

Amyloid beta (Aβ) aggregation is generally associated with Alzheimer’s onset. We have demonstrated that incubation of dopaminergic SH-SY5Y cells with an Aβ peptide fragment (an 11-mer composed of residues 25–35; Aβ (25–35)) results in elevated intracellular nitrosative stress and induces chemical mutation of protein disulfide isomerase (PDI), an endoplasmic reticulum-resident oxidoreductase chaperone. Furthermore, Aβ (25–35) provokes aggregation of both the minor and major biomarkers of Parkinson’s disease, namely, synphilin-1 and α-synuclein, respectively. Importantly, fluorescence studies demonstrate that Aβ (25–35) triggers colocalization of these Parkinsonian biomarkers to form Lewy-body-like aggregates, a key and irreversible milestone in the neurometabolic cascade leading to Parkinson’s disease. In addition, fluorescence assays also reveal direct, aggregation-seeding interactions between Aβ (25–35), PDI and α-synuclein, suggesting neuronal pathogenesis occurs via prion-type cross-transfectivity. These data indicate that the introduction of an Alzheimer’s-associated biomarker in dopaminergic cells is proliferative, with the percolative effect exercised via dual, independent, Parkinson-pathogenic pathways, one stress-derived and the other prion-like. The results define a novel molecular roadmap for Parkinsonian transfectivity via an Alzheimeric burden and reveal the involvement of PDI in amyloid beta induced Parkinson’s. We have also explored the ability of phytochemicals to intercept Aβ-driven Parkinson’s pathogenesis via multiple mechanisms. Results from these studies will be discussed..

This work is partly presented at 8th Edition of International Conference on Chemistry Education and Research August 27-28, 2018


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