An Innate Host Defense Protein b2-Microglobulin Keeps a Check on a-Synuclein amyloid Assembly: Implications in Parkinson's Disease

Amyloid formation due to protein misfolding has gained significant attention due to its association with neurodegenerative diseases. a-Synuclein (a-syn) is one such protein that undergoes a profound conformational switch to form higher order cross-(3-sheet structures, resulting in amyloid formation, which is linked to the pathophysiology of Parkinson's disease (PD). The present status of research on a-syn aggregation and PD reveals that the disease progression may be linked with many other diseases, such as kidney-related disorders. Unraveling the link between PD and non-neurological diseases may help in early detection and a better understanding of PD progression. Herein, we investigated the modulation of a-syn in the presence of (32-microglobulin ((32m), a structural protein associated with dialysis-related amyloidosis. We took a multi-disciplinary approach to establish that (32m mitigates amyloid formation by a-syn. Our fluorescence, microscopy and toxicity data demonstrated that sub-stoichiometric ratio of (32m drives a-syn into off-pathway non-toxic aggregates incompetent of transforming into amyloids. Using AlphaFold2 and all-atom MD simulation, we showed that the (3-strand segments ((31 and (32) of a-synuclein, which frequently engage in interactions within amyloid fibrils, interact with the last (3-strand at the C-terminal of (32m. The outcome of this study will unravel the yet unknown potential linkage of PD with kidney-related disorders. Insights from the cross-talk between two amyloidogenic proteins will lead to early diagnosis and new therapeutic approaches for treating Parkinson's disease. Finally, disruption of the nucleation process of a-syn amyloids by targeting the (31-(32 region will constitute a potential therapeutic approach for inhibiting amyloid formation. (c) 2023 Elsevier Ltd. All rights reserved.