Folding and Aggregation of Cu, Zn-Superoxide Dismutase

Broom, Helen R.; Primmer, Heather A.; Rumfeldt, Jessica A.O.; Stathopulos, Peter B.; Vassall, Kenrick A.; Hwang, Young-Mi; Meiering, Elizabeth M.

doi:10.5772/31629

Cited by 3 publications

(1 citation statement)

References 155 publications

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“…Both SALS and FALS display similar clinical symptoms, and the aggregation of superoxide dismutase 1 is connected to both. [7][8][9][10][11][12] About 233 mutants of SOD1 are reported to date that are spread throughout the structure of the SOD1 protein. [13][14][15] Misfolding of the WT SOD1 protein initiates aggregation and toxic amyloid fibril formation, which is associated with both SALS and FALS cases.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of the interaction of toxic SOD1 fibrils with two potent polyphenols: curcumin and quercetin

Sharma,

Tomar,

Deep

2023

Phys. Chem. Chem. Phys.

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Section: Introductionmentioning

confidence: 99%

Mechanism of the interaction of toxic SOD1 fibrils with two potent polyphenols: curcumin and quercetin

Sharma,

Tomar,

Deep

2023

Phys. Chem. Chem. Phys.

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

Bhatia

Modi

Sharma

et al. 2020

ACS Chem. Neurosci.

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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.

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Many roads lead to Rome? Multiple modes of Cu,Zn superoxide dismutase destabilization, misfolding and aggregation in amyotrophic lateral sclerosis

Broom

Rumfeldt

Meiering

2014

Essays in Biochemistry

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ALS (amyotrophic lateral sclerosis) is a fatal neurodegenerative syndrome characterized by progressive paralysis and motor neuron death. Although the pathological mechanisms that cause ALS remain unclear, accumulating evidence supports that ALS is a protein misfolding disorder. Mutations in Cu,Zn-SOD1 (copper/zinc superoxide dismutase 1) are a common cause of familial ALS. They have complex effects on different forms of SOD1, but generally destabilize the protein and enhance various modes of misfolding and aggregation. In addition, there is some evidence that destabilized covalently modified wild-type SOD1 may be involved in disease. Among the multitude of misfolded/aggregated species observed for SOD1, multiple species may impair various cellular components at different disease stages. Newly developed antibodies that recognize different structural features of SOD1 represent a powerful tool for further unravelling the roles of different SOD1 structures in disease. Evidence for similar cellular targets of misfolded/aggregated proteins, loss of cellular proteostasis and cell-cell transmission of aggregates point to common pathological mechanisms between ALS and other misfolding diseases, such as Alzheimer's, Parkinson's and prion diseases, as well as serpinopathies. The recent progress in understanding the molecular basis for these devastating diseases provides numerous avenues for developing urgently needed therapeutics.

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Folding and Aggregation of Cu, Zn-Superoxide Dismutase

Cited by 3 publications

References 155 publications

Mechanism of the interaction of toxic SOD1 fibrils with two potent polyphenols: curcumin and quercetin

Mechanism of the interaction of toxic SOD1 fibrils with two potent polyphenols: curcumin and quercetin

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

Many roads lead to Rome? Multiple modes of Cu,Zn superoxide dismutase destabilization, misfolding and aggregation in amyotrophic lateral sclerosis

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