Systematically perturbed folding patterns of amyotrophic lateral sclerosis (ALS)-associated SOD1 mutants

Lindberg, Mikael; Byström, Roberth; Boknäs, Niklas; Andersen, Peter M.; Oliveberg, Mikael

doi:10.1073/pnas.0501957102

Cited by 213 publications

(257 citation statements)

References 50 publications

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“…According to the proposed folding model of SOD1, the native, partially folded, apo monomer is in equilibrium with an unfolded monomeric state 47,48 . For some of the fALS mutant proteins, this equilibrium has been shown to be shifted towards the unfolded monomeric form 49,50 , which has also been suggested to be the starting material for the potentially toxic oligomeric species 42,49 . This unfolded monomer is likely identical to the SOD1 polypeptide that exits the ribosome, and should shift to the folded, dimeric E,Zn-SOD1 SH form upon zinc binding 50 .…”

Section: Discussionmentioning

confidence: 99%

In-cell NMR reveals potential precursor of toxic species from SOD1 fALS mutants

et al. 2014

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Mutations in the superoxide dismutase 1 (SOD1) gene are related to familial cases of amyotrophic lateral sclerosis (fALS). Here we exploit in-cell NMR to characterize the protein folding and maturation of a series of fALS-linked SOD1 mutants in human cells and to obtain insight into their behaviour in the cellular context, at the molecular level. The effect of various mutations on SOD1 maturation are investigated by changing the availability of metal ions in the cells, and by coexpressing the copper chaperone for SOD1, hCCS. We observe for most of the mutants the occurrence of an unstructured SOD1 species, unable to bind zinc. This species may be a common precursor of potentially toxic oligomeric species, that are associated with fALS. Coexpression of hCCS in the presence of copper restores the correct maturation of the SOD1 mutants and prevents the formation of the unstructured species, confirming that hCCS also acts as a molecular chaperone.

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Section: Discussionmentioning

confidence: 99%

In-cell NMR reveals potential precursor of toxic species from SOD1 fALS mutants

et al. 2014

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“…11B), suggesting that the BiP PBD domain is required for optimal binding to mutant SOD1. Discussion ALS-linked mutations destabilize the precursor monomer, weaken the dimer interface, or both (16), and promote aggregation (3). In keeping with mutant SOD1 folding abnormalities, herein we show that the constitutive expression of SOD1 G93A and SOD1 G85R , which are two of the most extensively characterized ALS-linked SOD1 mutants in transgenic rodents, are associated with a recruitment of key mediators of the UPR (6).…”

Section: Mutant Sod1 G93a But Not Hsod1 Wt or Msod1 Interacts With Bipmentioning

confidence: 99%

Spinal cord endoplasmic reticulum stress associated with a microsomal accumulation of mutant superoxide dismutase-1 in an ALS model

Kikuchi

Almer

Yamashita

et al. 2006

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

282

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Mutation in superoxide dismutase-1 (SOD1), which is a cause of ALS, alters the folding patterns of this protein. Accumulation of misfolded mutant SOD1 might activate endoplasmic reticulum (ER) stress pathways. Here we show that transgenic mice expressing ALS-linked SOD1 mutants exhibit molecular alterations indicative of a recruitment of ER's signaling machinery. We demonstrate by biochemical and morphological methods that mutant SOD1 accumulates inside the ER, where it forms insoluble high molecular weight species and interacts with the ER chaperone immunoglobulin-binding protein. These alterations are age-and regionspecific, because they develop over the course of the disease and occur in the affected spinal cord but not in the nonaffected cerebellum in transgenic mutant SOD1 mice. Our results suggest a toxic mechanism for mutant SOD1 by which this ubiquitously expressed pathogenic protein could affect motor neuron survival and contribute to the selective motor neuronal degeneration in ALS.neurodegeneration ͉ protein misfolding A LS is the most common adult-onset paralytic disease characterized by a loss of motor neurons in the cerebral cortex, brainstem, and spinal cord. Insights into the neurodegenerative mechanisms followed the discovery that dominant mutations in the gene for superoxide dismutase-1 (SOD1) cause familial ALS. Overexpression of SOD1 mutants in rodents recapitulates ALS clinical and pathological hallmarks through a toxic gain of function (1). Many mutations in SOD1 decrease its stability and increase its unfolding rates and propensity to aggregate (2). High molecular weight complexes of SOD1 are observed in mammalian cells and spinal cords of transgenic mice expressing this mutant protein (3). In these animals, intracellular ubiquitin-positive proteinaceous inclusions are also often seen in spinal cord motor neurons and, in some cases, in neighboring astrocytes (3-5). These findings posit that accumulation of misfolded mutant SOD1 could contribute to the demise of motor neurons.Endoplasmic reticulum (ER) stress signaling, otherwise known as the unfolded protein response (UPR), is triggered by an increased load of misfolded proteins in the organelle (6). Herein, we show that transgenic mice expressing mutant SOD1 exhibit age-and region-specific molecular alterations indicative of a broad recruitment of ER signaling pathways, including caspase-12, a prototypical ER cell death effector (7). We also show that mutant SOD1, and to a lesser extent wild-type SOD1 (SOD1 WT ), do accumulate in the ER. Within this organelle, mutant, but not SOD1 WT , forms high molecular weight species and interacts with the ER chaperone immunoglobulin-binding protein (BiP), which is a key component of the ER misfolded protein recognition machinery (6). The preferential accumulation of mutant SOD1 in the ER in the spinal cord cells and the ensuing stress response may represent novel aspects of motor neuron degeneration in this ALS model.

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“…We show that the net charge and the thermodynamic stability of SOD1, which both help to prevent aggregation of the protein [29,60,73,105], have increased during evolution of great ape SOD1. These two properties are known to correlate with the survival time in patients carrying SOD1…”

Section: Discussionmentioning

confidence: 99%

“…net charge and thermodynamic stability. These two properties have been shown to play a major role in aggregation of SOD1: Mutations in SOD1 that reduce net charge and stability correlate with more severe clinical outcome of the aging-triggered motor neuron disease ALS, characterized by pathological SOD1 aggregates and molecular oxidative stress [58][59][60][61].…”

Section: Computation Of Protein Propertiesmentioning

confidence: 99%

“…mutations that reduce stability and net charge of the protein to increase protein misfolding [60][107] are known to cause severe familial forms of ALS [35][61]. SOD1 mRNA levels are also elevated in sporadic ALS, so the role of SOD1 in the motor neuron disease is not limited to the familial cases [108].…”

Section: The Relationship To Als: Evolution Of Aging and Neurologicalmentioning

confidence: 99%

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Superoxide dismutase 1 is positively selected to minimize protein aggregation in great apes

Dasmeh

Kepp

2017

Cell. Mol. Life Sci.

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Systematically perturbed folding patterns of amyotrophic lateral sclerosis (ALS)-associated SOD1 mutants

Cited by 213 publications

References 50 publications

In-cell NMR reveals potential precursor of toxic species from SOD1 fALS mutants

In-cell NMR reveals potential precursor of toxic species from SOD1 fALS mutants

Spinal cord endoplasmic reticulum stress associated with a microsomal accumulation of mutant superoxide dismutase-1 in an ALS model

Superoxide dismutase 1 is positively selected to minimize protein aggregation in great apes

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