An Innate Host Defense Protein β2-Microglobulin Keeps a Check on α-Synuclein amyloid Assembly: Implications in Parkinson's Disease

Abstract

Amyloid formation due to protein misfolding has gained significant attention due to its association with neurodegenerative diseases. α-Synuclein (α-syn) is one such protein that undergoes a profound conformational switch to form higher order cross-β-sheet structures, resulting in amyloid formation, which is linked to the pathophysiology of Parkinson's disease (PD). The present status of research on α-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 α-syn in the presence of β2-microglobulin (β2m), a structural protein associated with dialysis-related amyloidosis. We took a multi-disciplinary approach to establish that β2m mitigates amyloid formation by α-syn. Our fluorescence, microscopy and toxicity data demonstrated that sub-stoichiometric ratio of β2m drives α-syn into off-pathway non-toxic aggregates incompetent of transforming into amyloids. Using AlphaFold2 and all-atom MD simulation, we showed that the β-strand segments (β1 and β2) of α-synuclein, which frequently engage in interactions within amyloid fibrils, interact with the last β-strand at the C-terminal of β2m. 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 α-syn amyloids by targeting the β1-β2 region will constitute a potential therapeutic approach for inhibiting amyloid formation.