Lack of evidence of monomer/misfolded superoxide dismutase‐1 in sporadic amyotrophic lateral sclerosis

Liu, Hsueh‐Ning; Sanelli, Teresa; Horne, Patrick; Pioro, Erik P.; Strong, Michael J.; Rogaeva, Ekaterina; Bilbao, Juan M.; Zinman, Lorne; Robertson, Janice

doi:10.1002/ana.21704

Cited by 77 publications

(85 citation statements)

References 26 publications

(44 reference statements)

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“…Finally, accumulation of misfolded SOD1 has been reported by several groups also in sporadic ALS (27,(41)(42)(43)(44)(45)(46)(47), although other groups have reached the opposite conclusion (48)(49)(50)(51). The identification of MIF as a cytosolic chaperone that stimulates the folding or refolding of misfolded SOD1 and inhibits the aggregation of mutant SOD1 in vivo suggests new avenues for therapy in ALS, mediated by increasing intracellular MIF levels in the nervous system.…”

Section: Discussionmentioning

confidence: 93%

Endogenous macrophage migration inhibitory factor reduces the accumulation and toxicity of misfolded SOD1 in a mouse model of ALS

Leyton-Jaimes

Benaim

Abu-Hamad

et al. 2016

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

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Mutations in superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease characterized by the loss of upper and lower motor neurons in the brain and spinal cord. It has been suggested that the toxicity of mutant SOD1 results from its misfolding and accumulation on the cytoplasmic faces of intracellular organelles, including the mitochondria and endoplasmic reticulum (ER) of ALS-affected tissues. Recently, macrophage migration inhibitory factor (MIF) was shown to directly inhibit the accumulation of misfolded SOD1 and its binding to intracellular membranes, but the role of endogenous MIF in modulating SOD1 misfolding in vivo remains unknown. To elucidate this role, we bred MIF-deficient mice with SOD1 G85R mice, which express a dismutase-inactive mutant of SOD1 and are considered a model of familial ALS. We found that the accumulation of misfolded SOD1, its association with mitochondrial and ER membranes, and the levels of sedimentable insoluble SOD1 aggregates were significantly higher in the spinal cords of SOD1 G85R -MIF −/− mice than in their SOD1 G85R -MIF +/+ littermates. Moreover, increasing MIF expression in neuronal cultures inhibited the accumulation of misfolded SOD1 and rescued from mutant SOD1-induced cell death. In contrast, the complete elimination of endogenous MIF accelerated disease onset and late disease progression and shortened the lifespan of the SOD1 G85R mutant mice. These findings indicate that MIF plays a significant role in the folding and misfolding of SOD1 in vivo, and they have implications for the potential therapeutic role of upregulating MIF within the nervous system to modulate the selective accumulation of misfolded SOD1.ALS | mutant SOD1 mouse | mutant SOD1 | misfolded SOD1 | MIF

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Section: Discussionmentioning

confidence: 93%

Endogenous macrophage migration inhibitory factor reduces the accumulation and toxicity of misfolded SOD1 in a mouse model of ALS

Leyton-Jaimes

Benaim

Abu-Hamad

et al. 2016

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

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“…Also, alterations in gene expression in the spinal cord were reported for mutant and WT SOD1 models but not in nontransgenic mice (89). Large aggregates of SOD1 are generally observed in fALS, but have only been reported for a subset of sALS cases (4,5,90), and are not detected by SEDI in sALS (90). However, small species of misfolded SOD1 have been proposed to be a common molecular signature in both sALS and fALS (91).…”

Section: Aggregation Arising From Holo Sod1 Is Not Different Frommentioning

confidence: 99%

Nonamyloid Aggregates Arising from Mature Copper/Zinc Superoxide Dismutases Resemble Those Observed in Amyotrophic Lateral Sclerosis

Hwang

Stathopulos

Dimmick

et al. 2010

Journal of Biological Chemistry

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Protein aggregation is a hallmark of many diseases, including amyotrophic lateral sclerosis (ALS) where aggregation of copper/zinc superoxide dismutase (SOD1) is implicated in pathogenesis. We report here that fully metallated (holo) SOD1 under physiologically relevant solution conditions can undergo changes in metallation and/or dimerization over time and form aggregates that do not exhibit classical characteristics of amyloid. The relevance of the observed aggregation to disease is demonstrated by structural and tinctorial analyses, including the novel observation of binding of an anti-SOD1 antibody that specifically recognizes aggregates in ALS patients and mice models. ALS-associated SOD1 mutations can promote aggregation but are not essential. The SOD1 aggregation is characterized by a lag phase, which is diminished by self-or cross-seeding and by heterogeneous nucleation. We interpret these findings in terms of an expanded aggregation mechanism consistent with other in vitro and in vivo findings that point to multiple pathways for the formation of toxic aggregates by different forms of SOD1. Amyotrophic lateral sclerosis (ALS)2 is a devastating, rapidly progressive, and invariably fatal neurodegenerative disease, characterized by motor neuron degeneration and paralysis (1). Approximately 10% of ALS cases are familial (fALS), the remaining cases being sporadic (sALS). The familial and sporadic diseases are clinically indistinguishable and so have been proposed to share common disease mechanisms (1). Mutations in copper/zinc superoxide dismutase (SOD1) account for ϳ20% of fALS and represent a major known cause of the disease. It is generally accepted that fALS-linked SOD1 mutations result in a toxic gain of function rather than a loss of function (1). Much attention has focused on toxic protein aggregation as causing ALS, analogous to pathogenic protein aggregation in other neurodegenerative diseases, including Alzheimer, Huntington, Parkinson, and prion diseases (1-5). SOD1 is present in aggregates in motor neurons of SOD1-linked fALS patients (3, 6) and mice models (3, 7-9) and in some sALS patients (4, 5, 10).Mature SOD1 is a homodimeric protein, with each ␤-barrel subunit containing one catalytic copper ion, one structural zinc ion, one intrasubunit disulfide bond, and two free cysteines (11) (see Fig. 1). More than 147 mainly missense mutations throughout the SOD1 structure have been associated with fALS. Aggregation has been reported previously only for immature (metal and/or disulfide deficient) or aberrant forms of SOD1, often under highly destabilizing conditions, which favor aggregation in general (12-19). The relevance to human disease of such aggregation is not known, nor is it known what forms of SOD1 may give rise to or be present in aggregates in patients (20). Mature (holo) SOD1 is a major form of SOD1 in cells for wild type and most mutant SOD1s (11). Although this form has been proposed to be incompatible with aggregation because of its very high stability (15, 21), several studies have rep...

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“…Inhibition of SOD causes accumulation of cellular superoxide radical and leads to free radical-mediated damage to mitochondrial membranes, the release of cytochrome c from mitochondria, and apoptosis of the cancer cells. It is concluded that targeting SOD1 may be a promising approach to the selective killing of cancer cells and that mechanism-based combinations of SOD inhibitors with free radical-producing agents may have clinical applications [23][24][25][26][27][28][29][30].…”

Section: Discussionmentioning

confidence: 99%

Role of Six Trans Membrane Protein of Prostate (STAMP) Proteins in Prostate Cancer- Relation with Survival Genes

Gonen-Korkmaz¹,

Sevin²,

Gökçe³

et al. 2017

J Cell Signal

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Prostate cancer studies focus on identification of androgen receptor (AR) regulated genes that are also highly expressed in the prostate. As a promising candidate, STAMP family genes STAMP1/STEAP2, STAMP2/STEAP4 and STEAP3 are involved in apoptosis and the cell cycle in metastatic prostate cancer. Vascular NADPH oxidase generates superoxide and other ROS, which stimulates IkappaB degradation and NF-kB activation by subunits of NADPH oxidases, namely p47phox and p67phox induced by different stimuli such as hydrogen peroxide. Hydrogen peroxide increased the expression levels of p67phox. They also have a role in redox-sensitive genes such as STAMP gene family. Flow cytometry analysis of LNCaP cells was performed using Annexin V staining and apoptotic index charts were drawn. STAMP1 and STAMP2 showed total anti-oxidant capacity versus control with hydrogen peroxide incubation. Using siRNA technology in LNCaP cells expressing mutant p53 silencing of p53 showed significant increase in MDM2 and decrease of caspase 9 mRNA levels at RT-PCR. Silencing of STAMP2, a significant decrease in p47phox was shown but STAMP1 silencing counteracted this effect on Cu/ZnSOD expression.As a conclusion, STAMP proteins have effects on oxidative stress-induced genes with significant and opposite changes.

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Lack of evidence of monomer/misfolded superoxide dismutase‐1 in sporadic amyotrophic lateral sclerosis

Cited by 77 publications

References 26 publications

Endogenous macrophage migration inhibitory factor reduces the accumulation and toxicity of misfolded SOD1 in a mouse model of ALS

Endogenous macrophage migration inhibitory factor reduces the accumulation and toxicity of misfolded SOD1 in a mouse model of ALS

Nonamyloid Aggregates Arising from Mature Copper/Zinc Superoxide Dismutases Resemble Those Observed in Amyotrophic Lateral Sclerosis

Role of Six Trans Membrane Protein of Prostate (STAMP) Proteins in Prostate Cancer- Relation with Survival Genes

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