Quercetin and Baicalein Act as Potent Antiamyloidogenic and Fibril Destabilizing Agents for SOD1 Fibrils

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that has been associated with the deposition of aggregates of superoxide dismutase 1 (SOD1). Effective therapeutics against SOD1 fibrillation is still an area of active research. Herein, we demonstrate the potential of two naturally occurring flavonoids (quercetin and baicalein) to inhibit fibrillation of wild-type SOD1 with the aid of a series of biophysical techniques. Our seeding experiments reveal that both of these flavonoids significantly affect the fibril elongation. Interestingly, our ThT binding assay, TEM, and SDS-PAGE experiments suggest that these flavonoids also disintegrate the fibrils into shorter fragments but do not completely depolymerize them into monomers. Binding parameters obtained from the analysis of UV−vis spectra suggest that these flavonoids bind moderately to native SOD1 dimer and have different binding sites. Docking of these flavonoids with a non-native monomer, non-native trimer, and oligomer derived from the 11-residue segment of SOD1 indicates that both quercetin and baicalein can bind to these species and thus can arrest the elongation of fibrils by blocking the fibrillar core regions on the intermediate species formed during aggregation of SOD1. MTT assay data revealed that both the flavonoids reduced the cytotoxicity of SOD1 fibrils. Experimental data also show the antiamyloidogenic potential of both flavonoids against A4V SOD1 mutant fibrillation. Thus, our findings may provide a direction for designing effective therapeutic agents against ALS which can act as promising antiamyloidogenic and fibril destabilizing agents.

Therapeutic Potential of Polyphenols in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

“…In vitro tests showed that quercetin glycosides, namely quercitrin and quercetin 3-beta-d-glucoside, inhibit misfolding and aggregation of SOD1 A4V mutant [ 132 ]. A similar effect on aggregation was observed with quercetin and baicalein [ 133 ]. Furthermore, preventive administration of quercetin in rats reduced oxidative stress, defective mitochondria, and brain cell death caused by aluminium exposure [ 134 ].…”

Amyotrophic Lateral Sclerosis: Proteins, Proteostasis, Prions, and Promises

“…Furthermore, ALS-associated mutations augment the fibrillation of SOD1 to different degrees (Furukawa et al, 2008 , 2010 ; Lang et al, 2012 ; Chan et al, 2013 ; Abdolvahabi et al, 2016 , 2017 ; McAlary et al, 2016 ), whereas some de novo mutations and PTMs have been shown to prevent (Abdolvahabi et al, 2015 ; Rasouli et al, 2017 ; Pokrishevsky et al, 2018 ) or enhance fibrillation (Shi et al, 2013 ). The Thioflavin-T assay has also been used to examine if SOD1 fibrillation can be lowered using chaperone proteins (Yerbury et al, 2013 ) or small molecules (Bhatia et al, 2015 , 2020 : Malik et al, 2019 ).…”

Dietary Plant Polyphenols as the Potential Drugs in Neurodegenerative Diseases: Current Evidence, Advances, and Opportunities

“…In neuro-2a cells transiently transfected with 16Q huntingtin (Htt) and 150 Htt, querce-tin increases cell viability and clears the mHtt aggregates via the upregulation of UPS activity [155]. In addition, quercetin binds to the SOD1 dimer, then blocks its fibrillization, and reduces the cytotoxicity of SOD1 fibrils in ALS [156,157]. Emerging evidence indicates that the excessive accumulation of metal ions generates amounts of ROS levels and induces neurotoxicity, which favours the pathological process in various neurodegenerative diseases [158][159][160], while the treatment of quercetin improves the viability and inhibits the proinflammatory responses via inhibiting the production of ROS levels and its resultant apoptosis [161,162].…”