SOD1 Aggregation and ALS: Role of Metallation States and Disulfide Status

Sheng, Yinghong; Chattopadhyay, Madhuri; Whitelegge, Jaulian; Valentine, Joan Selverstone

doi:10.2174/1568026611212220010

Cited by 97 publications

(70 citation statements)

References 98 publications

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“…Unlike the mature form of this antioxidant enzyme, which is highly stable, apoSOD1 2SH misfolds and aggregates in vitro (14,36,37), and may be a primary cause of toxicity in vivo (38). Thus, it is of considerable interest to characterize the free energy landscape of both WT and disease mutant forms of the protein as a first step toward understanding the initial stages of disease progression.…”

Section: Discussionmentioning

confidence: 99%

Probing the free energy landscapes of ALS disease mutants of SOD1 by NMR spectroscopy

Sekhar

Rumfeldt

Broom

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Section: Discussionmentioning

confidence: 99%

Probing the free energy landscapes of ALS disease mutants of SOD1 by NMR spectroscopy

Sekhar

Rumfeldt

Broom

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…1). A key feature of this system is that the immature apoSOD1 monomer, which is also implicated as a precursor in human pathology (9)(10)(11)(12), needs to be globally unfolded to fibrillate in vitro (7) (Fig. 1).…”

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confidence: 99%

SOD1 aggregation in ALS mice shows simplistic test tube behavior

Lang

Zetterström

Brännström

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

123

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A longstanding challenge in studies of neurodegenerative disease has been that the pathologic protein aggregates in live tissue are not amenable to structural and kinetic analysis by conventional methods. The situation is put in focus by the current progress in demarcating protein aggregation in vitro, exposing new mechanistic details that are now calling for quantitative in vivo comparison. In this study, we bridge this gap by presenting a direct comparison of the aggregation kinetics of the ALS-associated protein superoxide dismutase 1 (SOD1) in vitro and in transgenic mice. The results based on tissue sampling by quantitative antibody assays show that the SOD1 fibrillation kinetics in vitro mirror with remarkable accuracy the spinal cord aggregate buildup and disease progression in transgenic mice. This similarity between in vitro and in vivo data suggests that, despite the complexity of live tissue, SOD1 aggregation follows robust and simplistic rules, providing new mechanistic insights into the ALS pathology and organism-level manifestation of protein aggregation phenomena in general.superoxide dismutase 1 | aggregation | transgenic mice | aggregation kinetics

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“…We previously reported a procedure for in vitro aggregation of authentic ALS-mutant and wild-type SOD1 proteins into cross-␤-sheet amyloid fibrils under mild conditions similar to those present in human cells (31,33). In this model system, both wild-type and ALS-mutant SOD1 proteins were found to aggregate readily, adopting amyloid fibrillar structure as monitored using dyes such as thioflavin T that fluoresce when bound to amyloid fibrils (31).…”

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confidence: 99%

The Disulfide Bond, but Not Zinc or Dimerization, Controls Initiation and Seeded Growth in Amyotrophic Lateral Sclerosis-linked Cu,Zn Superoxide Dismutase (SOD1) Fibrillation

Chattopadhyay

Nwadibia

Strong

et al. 2015

Journal of Biological Chemistry

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Aggregation of copper-zinc superoxide dismutase (SOD1) is a defining feature of familial ALS caused by inherited mutations in the sod1 gene, and misfolded and aggregated forms of wildtype SOD1 are found in both sporadic and familial ALS cases. Mature SOD1 owes its exceptional stability to a number of posttranslational modifications as follows: formation of the intramolecular disulfide bond, binding of copper and zinc, and dimerization. Loss of stability due to the failure to acquire one or more of these modifications is proposed to lead to aggregation in vivo. Previously, we showed that the presence of apo-, disulfide-reduced SOD1, the most immature form of SOD1, results in initiation of fibrillation of more mature forms that have an intact Cys-57-Cys-146 disulfide bond and are partially metallated. In this study, we examine the ability of each of the above post-translational modifications to modulate fibril initiation and seeded growth. Cobalt or zinc binding, despite conferring great structural stability, neither inhibits the initiation propensity of disulfide-reduced SOD1 nor consistently protects disulfide-oxidized SOD1 from being recruited into growing fibrils across wild-type and a number of ALS mutants. In contrast, reduction of the disulfide bond, known to be necessary for fibril initiation, also allows for faster recruitment during seeded amyloid growth. These results identify separate factors that differently influence seeded growth and initiation and indicate a lack of correlation between the overall thermodynamic stability of partially mature SOD1 states and their ability to initiate fibrillation or be recruited by a growing fibril. Familial amyotrophic lateral sclerosis (FALS)3 caused by mutations in the SOD1 gene shows similarities to other members of the large class of neurodegenerative disorders that are characterized by gradual aggregation of specific proteins and subsequent cell death in characteristic regions of the central nervous system. Some prominent examples are amyloid-␤ deposits in Alzheimer disease, ␣-synuclein and hyperphosphorylated Tau protein deposits in Parkinson disease, prion protein deposits in the transmissible spongiform encephalopathies, and huntingtin deposits in Huntington disease (1). In the case of SOD1-linked FALS, protein deposits have been identified in affected tissues from patients and from ALS-SOD1 transgenic mice consisting largely of aggregated copper,zinc superoxide dismutase protein (Cu,Zn-SOD, SOD1 protein).Our current understanding of this class of diseases is that the implicated proteins misfold, aggregate, and ultimately deposit as extracellular plaques or intracellular inclusions in the afflicted regions of the CNS. Although the exact structures contributing to these heterogeneous protein aggregates are unknown, such diseases are nevertheless usually referred to as "amyloid diseases" because fibrillar properties characteristic of cross-␤-sheet amyloid are often detected in them and because each of the isolated proteins implicated in causing disease shows a...

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SOD1 Aggregation and ALS: Role of Metallation States and Disulfide Status

Cited by 97 publications

References 98 publications

Probing the free energy landscapes of ALS disease mutants of SOD1 by NMR spectroscopy

Probing the free energy landscapes of ALS disease mutants of SOD1 by NMR spectroscopy

SOD1 aggregation in ALS mice shows simplistic test tube behavior

The Disulfide Bond, but Not Zinc or Dimerization, Controls Initiation and Seeded Growth in Amyotrophic Lateral Sclerosis-linked Cu,Zn Superoxide Dismutase (SOD1) Fibrillation

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