Amyloid fibril structures and ferroptosis activation induced by ALS-causing SOD1 mutations

Over 200 genetic mutations in copper-zinc superoxide dismutase (SOD1) have been linked to amyotrophic lateral sclerosis (ALS). Among these, two ALS-causing mutants, histidine-46→arginine (H46R) and glycine-85→arginine (G85R), exhibit a decreased capacity to bind metal ions. Here, we report two cryo-...

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Veröffentlicht in:Science advances 2024-11, Vol.10 (44), p.eado8499
Hauptverfasser: Wang, Li-Qiang, Ma, Yeyang, Zhang, Mu-Ya, Yuan, Han-Ye, Li, Xiang-Ning, Xia, Wencheng, Zhao, Kun, Huang, Xi, Chen, Jie, Li, Dan, Zou, Liangyu, Wang, Zhengzhi, Le, Weidong, Liu, Cong, Liang, Yi
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container_issue 44
container_start_page eado8499
container_title Science advances
container_volume 10
creator Wang, Li-Qiang
Ma, Yeyang
Zhang, Mu-Ya
Yuan, Han-Ye
Li, Xiang-Ning
Xia, Wencheng
Zhao, Kun
Huang, Xi
Chen, Jie
Li, Dan
Zou, Liangyu
Wang, Zhengzhi
Le, Weidong
Liu, Cong
Liang, Yi
description Over 200 genetic mutations in copper-zinc superoxide dismutase (SOD1) have been linked to amyotrophic lateral sclerosis (ALS). Among these, two ALS-causing mutants, histidine-46→arginine (H46R) and glycine-85→arginine (G85R), exhibit a decreased capacity to bind metal ions. Here, we report two cryo-electron microscopy structures of amyloid fibrils formed by H46R and G85R. These mutations lead to the formation of amyloid fibrils with unique structures distinct from those of the native fibril. The core of these fibrils features a serpentine arrangement with seven or eight β strands, secured by a hydrophobic cavity and a salt bridge between arginine-85 and aspartic acid-101 in the G85R fibril. We demonstrate that these mutant fibrils are notably more toxic and capable of promoting the aggregation of wild-type SOD1 more effectively, causing mitochondrial impairment and activating ferroptosis in cell cultures, compared to wild-type SOD1 fibrils. Our study provides insights into the structural mechanisms by which SOD1 mutants aggregate and induce cytotoxicity in ALS.
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Among these, two ALS-causing mutants, histidine-46→arginine (H46R) and glycine-85→arginine (G85R), exhibit a decreased capacity to bind metal ions. Here, we report two cryo-electron microscopy structures of amyloid fibrils formed by H46R and G85R. These mutations lead to the formation of amyloid fibrils with unique structures distinct from those of the native fibril. The core of these fibrils features a serpentine arrangement with seven or eight β strands, secured by a hydrophobic cavity and a salt bridge between arginine-85 and aspartic acid-101 in the G85R fibril. We demonstrate that these mutant fibrils are notably more toxic and capable of promoting the aggregation of wild-type SOD1 more effectively, causing mitochondrial impairment and activating ferroptosis in cell cultures, compared to wild-type SOD1 fibrils. 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subjects Amyloid - metabolism
Amyotrophic Lateral Sclerosis - genetics
Amyotrophic Lateral Sclerosis - metabolism
Amyotrophic Lateral Sclerosis - pathology
Biochemistry
Biomedicine and Life Sciences
Biophysics
Cryoelectron Microscopy
Ferroptosis - genetics
Humans
Mitochondria - metabolism
Models, Molecular
Mutation
SciAdv r-articles
Superoxide Dismutase-1 - chemistry
Superoxide Dismutase-1 - genetics
Superoxide Dismutase-1 - metabolism
title Amyloid fibril structures and ferroptosis activation induced by ALS-causing SOD1 mutations
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