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Статті в журналах з теми "HSOD1"

Автор: Grafiati

Опубліковано: 10 березня 2023

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1

Bouldin, Samantha D., Maxwell A. Darch, P. John Hart, and Caryn E. Outten. "Redox properties of the disulfide bond of human Cu,Zn superoxide dismutase and the effects of human glutaredoxin 1." Biochemical Journal 446, no. 1 (July 27, 2012): 59–67. http://dx.doi.org/10.1042/bj20120075.

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Анотація:

The intramolecular disulfide bond in hSOD1 [human SOD1 (Cu,Zn superoxide dismutase 1)] plays a key role in maintaining the protein's stability and quaternary structure. In mutant forms of SOD1 that cause familial ALS (amyotrophic lateral sclerosis), this disulfide bond is more susceptible to chemical reduction, which may lead to destabilization of the dimer and aggregation. During hSOD1 maturation, disulfide formation is catalysed by CCS1 (copper chaperone for SOD1). Previous studies in yeast demonstrate that the yeast GSH/Grx (glutaredoxin) redox system promotes reduction of the hSOD1 disulfide in the absence of CCS1. In the present study, we probe further the interaction between hSOD1, GSH and Grxs to provide mechanistic insight into the redox kinetics and thermodynamics of the hSOD1 disulfide. We demonstrate that hGrx1 (human Grx1) uses a monothiol mechanism to reduce the hSOD1 disulfide, and the GSH/hGrx1 system reduces ALS mutant SOD1 at a faster rate than WT (wild-type) hSOD1. However, redox potential measurements demonstrate that the thermodynamic stability of the disulfide is not consistently lower in ALS mutants compared with WT hSOD1. Furthermore, the presence of metal cofactors does not influence the disulfide redox potential. Overall, these studies suggest that differences in the GSH/hGrx1 reaction rate with WT compared with ALS mutant hSOD1 and not the inherent thermodynamic stability of the hSOD1 disulfide bond may contribute to the greater pathogenicity of ALS mutant hSOD1.

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2

Coelho, Fernando R., Asif Iqbal, Edlaine Linares, Daniel F. Silva, Filipe S. Lima, Iolanda M. Cuccovia, and Ohara Augusto. "Oxidation of the Tryptophan 32 Residue of Human Superoxide Dismutase 1 Caused by Its Bicarbonate-dependent Peroxidase Activity Triggers the Non-amyloid Aggregation of the Enzyme." Journal of Biological Chemistry 289, no. 44 (September 18, 2014): 30690–701. http://dx.doi.org/10.1074/jbc.m114.586370.

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Анотація:

The role of oxidative post-translational modifications of human superoxide dismutase 1 (hSOD1) in the amyotrophic lateral sclerosis (ALS) pathology is an attractive hypothesis to explore based on several lines of evidence. Among them, the remarkable stability of hSOD1WT and several of its ALS-associated mutants suggests that hSOD1 oxidation may precede its conversion to the unfolded and aggregated forms found in ALS patients. The bicarbonate-dependent peroxidase activity of hSOD1 causes oxidation of its own solvent-exposed Trp32 residue. The resulting products are apparently different from those produced in the absence of bicarbonate and are most likely specific for simian SOD1s, which contain the Trp32 residue. The aims of this work were to examine whether the bicarbonate-dependent peroxidase activity of hSOD1 (hSOD1WT and hSOD1G93A mutant) triggers aggregation of the enzyme and to comprehend the role of the Trp32 residue in the process. The results showed that Trp32 residues of both enzymes are oxidized to a similar extent to hSOD1-derived tryptophanyl radicals. These radicals decayed to hSOD1-N-formylkynurenine and hSOD1-kynurenine or to a hSOD1 covalent dimer cross-linked by a ditryptophan bond, causing hSOD1 unfolding, oligomerization, and non-amyloid aggregation. The latter process was inhibited by tempol, which recombines with the hSOD1-derived tryptophanyl radical, and did not occur in the absence of bicarbonate or with enzymes that lack the Trp32 residue (bovine SOD1 and hSOD1W32F mutant). The results support a role for the oxidation products of the hSOD1-Trp32 residue, particularly the covalent dimer, in triggering the non-amyloid aggregation of hSOD1.

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3

Zhang, Kun, Yuejuan Zhang, Jing Zi, Xiaochang Xue, and Yi Wan. "Production of Human Cu,Zn SOD with Higher Activity and Lower Toxicity inE. colivia Mutation of Free Cysteine Residues." BioMed Research International 2017 (2017): 1–12. http://dx.doi.org/10.1155/2017/4817376.

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Анотація:

Although, as an antioxidant enzyme, human Cu,Zn superoxide dismutase 1 (hSOD1) can mitigate damage to cell components caused by free radicals generated by aerobic metabolism, large-scale manufacturing and clinical use of hSOD1 are still limited by the challenge of rapid and inexpensive production of high-quality eukaryotic hSOD1 in recombinant forms. We have demonstrated previously that it is a promising strategy to increase the expression levels of soluble hSOD1 so as to increase hSOD1 yields inE. coli. In this study, a wild-type hSOD1 (wtSOD1) and three mutant SOD1s (mhSOD1s), in which free cysteines were substituted with serine, were constructed and their expression in soluble form was measured. Results show that the substitution of Cys111 (mhSOD1/C111S) increased the expression of soluble hSOD1 inE. coliwhereas substitution of the internal Cys6 (mhSOD1/C6S) decreased it.Besides, raised levels of soluble expression led to an increase in hSOD1 yields. In addition, mhSOD1/C111S expressed at a higher soluble level showed lower toxicity and stronger whitening and antiradiation activities than those of wtSOD1. Taken together, our data demonstrate that C111S mutation in hSOD1 is an effective strategy to develop new SOD1-associated reagents and that mhSOD1/C111S is a satisfactory candidate for large-scale production.

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4

Álvarez-Zaldiernas, Cristina, Jun Lu, Yujuan Zheng, Hongqian Yang, Juan Blasi, Carles Solsona, and Arne Holmgren. "Cellular Redox Systems Impact the Aggregation of Cu,Zn Superoxide Dismutase Linked to Familial Amyotrophic Lateral Sclerosis." Journal of Biological Chemistry 291, no. 33 (June 3, 2016): 17197–208. http://dx.doi.org/10.1074/jbc.m115.708230.

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Анотація:

Protein misfolding is implicated in neurodegenerative diseases such as ALS, where mutations of superoxide dismutase 1 (SOD1) account for about 20% of the inherited mutations. Human SOD1 (hSOD1) contains four cysteines, including Cys57 and Cys146, which have been linked to protein stability and folding via forming a disulfide bond, and Cys6 and Cys111 as free thiols. But the roles of the cellular oxidation-reduction (redox) environment in SOD1 folding and aggregation are not well understood. Here we explore the effects of cellular redox systems on the aggregation of hSOD1 proteins. We found that the known hSOD1 mutations G93A and A4V increased the capability of the thioredoxin and glutaredoxin systems to reduce hSOD1 compared with wild-type hSOD1. Treatment with inhibitors of these redox systems resulted in an increase of hSOD1 aggregates in the cytoplasm of cells transfected with mutants but not in cells transfected with wild-type hSOD1 or those containing a secondary C111G mutation. This aggregation may be coupled to changes in the redox state of the G93A and A4V mutants upon mild oxidative stress. These results strongly suggest that the thioredoxin and glutaredoxin systems are the key regulators for hSOD1 aggregation and may play critical roles in the pathogenesis of ALS.

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5

FENG, LIN, Yan Dan Dan, Chen Ya Wen, Fletcher Emmanuella E, Shi Hai Feng, Han Bang Xing, and Zhou Yang. "Cloning, purification and enzymatic characterization of recombinant human Superoxide dismutase 1 expressed in Escherichia coli." Acta Biochimica Polonica 65, no. 2 (July 8, 2018): 235–40. http://dx.doi.org/10.18388/abp.2017_2350.

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Анотація:

Superoxide dismutase 1 (SOD1) is a metalloenzyme that catalyzes disproportion-action superoxide into molecular oxygen and hydrogen peroxide. In this study, the human SOD1 (hSOD1) gene was cloned, expressed, and purified. The hSOD1 gene was amplified from a pool of Bxpc3 cell cDNAs by PCR and cloned into expression vector pET-28a (+). The recombinant soluble hSOD1 was expressed in E.coli BL21 (DE3) at 37°C and purified by Nickel column affinity chromatography. The soluble hSOD1 was produced with a yield of 5.9 ug/mL medium. Considering that metal ions have a certain influence on the structure and activity of protein, we researched the influences of different concentrations of Cu2+ and Zn2+ on hSOD1 activity at induction and the time of activity detection. The results implied Cu2+ and Zn2+ can’t enhance SOD1 expression, however can improve the catalytic activity at induction. Furthermore, most of bivalent cations have an improve effect on enzyme activity at the time of detection.

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6

Islam, Rafique, Emily L. Kumimoto, Hong Bao, and Bing Zhang. "ALS-linked SOD1 in glial cells enhances ß-N-Methylamino L-Alanine (BMAA)-induced toxicity in Drosophila." F1000Research 1 (November 9, 2012): 47. http://dx.doi.org/10.12688/f1000research.1-47.v1.

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Анотація:

Environmental factors have been implicated in the etiology of a number of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). However, the role of environmental agents in ALS remains poorly understood. To this end, we used transgenic fruit flies (Drosophila melanogaster) to explore the interaction between mutant superoxide dismutase 1 (SOD1) and chemicals such as ß-N-methylamino L-alanine (BMAA), the herbicide agent paraquat, and superoxide species. We expressed ALS-linked human SOD1 (hSOD1A4V, and hSOD1G85R), hSOD1wt as well as the Drosophila native SOD1 (dSOD1) in motoneurons (MNs) or in glial cells alone and simultaneously in both types of cells. We then examined the effect of BMAA (3 mM), paraquat (20 mM), and hydrogen peroxide (H2O2, 1%) on the lifespan of SOD1-expressing flies. Our data show that glial expression of mutant and wild type hSOD1s reduces the ability of flies to climb. Further, we show that while all three chemicals significantly shorten the lifespan of flies, mutant SOD1 does not have a significant additional effect on the lifespan of flies fed on paraquat, but further shortens the lifespan of flies fed on H2O2. Finally, we show that BMAA shows a dramatic cell-type specific effect with mutant SOD1. Flies with expression of mutant hSOD1 in MNs survived longer on BMAA compared to control flies. In contrast, BMAA significantly shortened the lifespan of flies expressing mutant hSOD1 in glia. Consistent with a neuronal protection role, flies expressing these mutant hSOD1s in both MNs and glia also lived longer. Hence, our studies reveal a synergistic effect of mutant SOD1 with H2O2 and novel roles for mutant hSOD1s in neurons to reduce BMAA toxicity and in glia to enhance the toxicity of BMAA in flies.

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7

Martin, Lee J., Danya A. Adams, Mark V. Niedzwiecki, and Margaret Wong. "Aberrant DNA and RNA Methylation Occur in Spinal Cord and Skeletal Muscle of Human SOD1 Mouse Models of ALS and in Human ALS: Targeting DNA Methylation Is Therapeutic." Cells 11, no. 21 (October 31, 2022): 3448. http://dx.doi.org/10.3390/cells11213448.

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Анотація:

Amyotrophic lateral sclerosis (ALS) is a fatal disease. Skeletal muscles and motor neurons (MNs) degenerate. ALS is a complex disease involving many genes in multiple tissues, the environment, cellular metabolism, and lifestyles. We hypothesized that epigenetic anomalies in DNA and RNA occur in ALS and examined this idea in: (1) mouse models of ALS, (2) human ALS, and (3) mouse ALS with therapeutic targeting of DNA methylation. Human superoxide dismutase-1 (hSOD1) transgenic (tg) mice were used. They expressed nonconditionally wildtype (WT) and the G93A and G37R mutant variants or skeletal muscle-restricted WT and G93A and G37R mutated forms. Age-matched non-tg mice were controls. hSOD1 mutant mice had increased DNA methyltransferase enzyme activity in spinal cord and skeletal muscle and increased 5-methylcytosine (5mC) levels. Genome-wide promoter CpG DNA methylation profiling in skeletal muscle of ALS mice identified hypermethylation notably in cytoskeletal genes. 5mC accumulated in spinal cord MNs and skeletal muscle satellite cells in mice. Significant increases in DNA methyltransferase-1 (DNMT1) and DNA methyltransferase-3A (DNMT3A) levels occurred in spinal cord nuclear and chromatin bound extracts of the different hSOD1 mouse lines. Mutant hSOD1 interacted with DNMT3A in skeletal muscle. 6-methyladenosine (6mA) RNA methylation was markedly increased or decreased in mouse spinal cord depending on hSOD1-G93A model, while fat mass and obesity associated protein was depleted and methyltransferase-like protein 3 was increased in spinal cord and skeletal muscle. Human ALS spinal cord had increased numbers of MNs and interneurons with nuclear 5mC, motor cortex had increased 5mC-positive neurons, while 6mA was severely depleted. Treatment of hSOD1-G93A mice with DNMT inhibitor improved motor function and extended lifespan by 25%. We conclude that DNA and RNA epigenetic anomalies are prominent in mouse and human ALS and are potentially targetable for disease-modifying therapeutics.

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8

Self, Wade K., Kathleen Schoch, James Bollinger, Tracy Cole, Holly Kordasiewicz, Randall Bateman, and Timothy Miller. "2342 Protein production as an early pharmacodynamics biomarker for RNA-targeting therapies." Journal of Clinical and Translational Science 2, S1 (June 2018): 24. http://dx.doi.org/10.1017/cts.2018.110.

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OBJECTIVES/SPECIFIC AIMS: We aimed to develop an assay to measure new protein synthesis after Antisense Oligonucleotide treatment, which we hypothesized to be the earliest biochemical identification of RNA-targeting therapy efficacy. METHODS/STUDY POPULATION: We treated 2 transgenic animal models expressing proteins implicated in neurodegenerative disease: human tau protein (hTau) and human superoxide dismutase 1 (hSOD1), with ASO against these mRNA transcripts. Animals received isotope-labeled 13C6-Leucine via drinking water to label newly synthesized proteins. We assayed target protein synthesis and concentration after ASO treatment to determine the earliest identification of ASO target engagement. RESULTS/ANTICIPATED RESULTS: hTau ASO treatment in transgenic mice lowered hTau protein concentration 23 days post-treatment in cortex (95% CI: 0.05%–64.0% reduction). In the same tissue, we observed lowering of hTau protein synthesis as early as 13 days (95% CI: 29.4%–123%). In hSOD1 transgenic rats, we observed lowering of 13C6-leucine-labeled hSOD1 in the cerebrospinal fluid 30 days after ASO treatment compared with inactive ASO control (95% CI: 12.0%–48.4%). DISCUSSION/SIGNIFICANCE OF IMPACT: In progressive neurodegenerative diseases, it is crucial to develop measurements that identify treatment efficacy early to improve patient outcomes. These data support the use of stable isotope labeling of amino acids to measure new protein synthesis as an early pharmacodynamics measurement for therapies that target RNA and inhibit the translation of proteins.

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9

Brasil, Aline de Araújo, Mariana Dias Castela de Carvalho, Ellen Gerhardt, Daniela Dias Queiroz, Marcos Dias Pereira, Tiago Fleming Outeiro, and Elis Cristina Araujo Eleutherio. "Characterization of the activity, aggregation, and toxicity of heterodimers of WT and ALS-associated mutant Sod1." Proceedings of the National Academy of Sciences 116, no. 51 (December 3, 2019): 25991–6000. http://dx.doi.org/10.1073/pnas.1902483116.

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Mutations in Cu/Zn superoxide dismutase (Sod1) have been reported in both familial and sporadic amyotrophic lateral sclerosis (ALS). In this study, we investigated the behavior of heteromeric combinations of wild-type (WT) and mutant Sod1 proteins A4V, L38V, G93A, and G93C in human cells. We showed that both WT and mutant Sod1 formed dimers and oligomers, but only mutant Sod1 accumulated in intracellular inclusions. Coexpression of WT and hSod1 mutants resulted in the formation of a larger number of intracellular inclusions per cell than that observed in cells coexpressing WT or mutant hSod1. The number of inclusions was greater in cells expressing A4V hSod1. To eliminate the contribution of endogenous Sod1, and better evaluate the effect of ALS-associated mutant Sod1 expression, we expressed human Sod1 WT and mutants in human cells knocked down for endogenous Sod1 (Sod1-KD), and insod1Δyeast cells. Using Sod1-KD cells we found that the WT–A4V heteromers formed higher molecular weight species compared with A4V and WT homomers. Using the yeast model, in conditions of chronological aging, we concluded that cells expressing Sod1 heterodimers showed decreased antioxidant activity, increased oxidative damage, reduced longevity, and oxidative stress-induced mutant Sod1 aggregation. In addition, we also found that ALS-associated Sod1 mutations reduced nuclear localization and, consequently, impaired the antioxidant response, suggesting this change in localization may contribute to disease in familial ALS. Overall, our study provides insight into the molecular underpinnings of ALS and may open avenues for the design of future therapeutic strategies.

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10

Queiroz, Raphael F., Verônica Paviani, Fernando R. Coelho, Emerson F. Marques, Paolo Di Mascio, and Ohara Augusto. "The carbonylation and covalent dimerization of human superoxide dismutase 1 caused by its bicarbonate-dependent peroxidase activity is inhibited by the radical scavenger tempol." Biochemical Journal 455, no. 1 (September 13, 2013): 37–46. http://dx.doi.org/10.1042/bj20130180.

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Анотація:

The nitroxide tempol inhibited the carbonylation and covalent dimerization of human superoxide dismutase 1 caused by its bicarbonate-dependent peroxidase activity. Tempol acted by scavenging the produced carbonate radical and by recombining with hSOD1-Trp32• radicals as indicated by MS/MS evidence.

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11

Banci, Lucia, Francesca Cantini, Tatiana Kozyreva, and Jeffrey T. Rubino. "Mechanistic Aspects of hSOD1 Maturation from the Solution Structure of CuI-Loaded hCCS Domain 1 and Analysis of Disulfide-Free hSOD1 Mutants." ChemBioChem 14, no. 14 (April 26, 2013): 1839–44. http://dx.doi.org/10.1002/cbic.201300042.

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12

Huang, Yunpeng, Zhihao Wu, and Bing Zhou. "hSOD1 Promotes Tau Phosphorylation and Toxicity in the Drosophila Model." Journal of Alzheimer's Disease 45, no. 1 (March 3, 2015): 235–44. http://dx.doi.org/10.3233/jad-141608.

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13

Stella, Roberto, Raphael Severino Bonadio, Stefano Cagnin, Maria Lina Massimino, Alessandro Bertoli, and Caterina Peggion. "Perturbations of the Proteome and of Secreted Metabolites in Primary Astrocytes from the hSOD1(G93A) ALS Mouse Model." International Journal of Molecular Sciences 22, no. 13 (June 29, 2021): 7028. http://dx.doi.org/10.3390/ijms22137028.

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Анотація:

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease whose pathophysiology is largely unknown. Despite the fact that motor neuron (MN) death is recognized as the key event in ALS, astrocytes dysfunctionalities and neuroinflammation were demonstrated to accompany and probably even drive MN loss. Nevertheless, the mechanisms priming astrocyte failure and hyperactivation are still obscure. In this work, altered pathways and molecules in ALS astrocytes were unveiled by investigating the proteomic profile and the secreted metabolome of primary spinal cord astrocytes derived from transgenic ALS mouse model overexpressing the human (h)SOD1(G93A) protein in comparison with the transgenic counterpart expressing hSOD1(WT) protein. Here we show that ALS primary astrocytes are depleted of proteins—and of secreted metabolites—involved in glutathione metabolism and signaling. The observed increased activation of Nf-kB, Ebf1, and Plag1 transcription factors may account for the augmented expression of proteins involved in the proteolytic routes mediated by proteasome or endosome–lysosome systems. Moreover, hSOD1(G93A) primary astrocytes also display altered lipid metabolism. Our results provide novel insights into the altered molecular pathways that may underlie astrocyte dysfunctionalities and altered astrocyte–MN crosstalk in ALS, representing potential therapeutic targets to abrogate or slow down MN demise in disease pathogenesis.

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14

Alexander, Guillermo M., Terry D. Heiman-Patterson, Frank Bearoff, Roger B. Sher, Laura Hennessy, Shannon Terek, Nicole Caccavo, Gregory A. Cox, Vivek M. Philip, and Elizabeth A. Blankenhorn. "Identification of quantitative trait loci for survival in the mutant dynactin p150Glued mouse model of motor neuron disease." PLOS ONE 17, no. 9 (September 15, 2022): e0274615. http://dx.doi.org/10.1371/journal.pone.0274615.

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Анотація:

Amyotrophic lateral sclerosis (ALS) is the most common degenerative motor neuron disorder. Although most cases of ALS are sporadic, 5–10% of cases are familial, with mutations associated with over 40 genes. There is variation of ALS symptoms within families carrying the same mutation; the disease may develop in one sibling and not in another despite the presence of the mutation in both. Although the cause of this phenotypic variation is unknown, it is likely related to genetic modifiers of disease expression. The identification of ALS causing genes has led to the development of transgenic mouse models of motor neuron disease. Similar to families with familial ALS, there are background-dependent differences in disease phenotype in transgenic mouse models of ALS suggesting that, as in human ALS, differences in phenotype may be ascribed to genetic modifiers. These genetic modifiers may not cause ALS rather their expression either exacerbates or ameliorates the effect of the mutant ALS causing genes. We have reported that in both the G93A-hSOD1 and G59S-hDCTN1 mouse models, SJL mice demonstrated a more severe phenotype than C57BL6 mice. From reciprocal intercrosses between G93A-hSOD1 transgenic mice on SJL and C57BL6 strains, we identified a major quantitative trait locus (QTL) on mouse chromosome 17 that results in a significant shift in lifespan. In this study we generated reciprocal intercrosses between transgenic G59S-hDCTN1 mice on SJL and C57BL6 strains and identified survival QTLs on mouse chromosomes 17 and 18. The chromosome 17 survival QTL on G93A-hSOD1 and G59S-hDCTN1 mice partly overlap, suggesting that the genetic modifiers located in this region may be shared by these two ALS models despite the fact that motor neuron degeneration is caused by mutations in different proteins. The overlapping region contains eighty-seven genes with non-synonymous variations predicted to be deleterious and/or damaging. Two genes in this segment, NOTCH3 and Safb/SAFB1, have been associated with motor neuron disease. The identification of genetic modifiers of motor neuron disease, especially those modifiers that are shared by SOD1 and dynactin-1 transgenic mice, may result in the identification of novel targets for therapies that can alter the course of this devastating illness.

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15

Linseman, Daniel A., Aimee N. Winter, and Heather M. Wilkins. "The 2-Oxoglutarate Carrier Is S-Nitrosylated in the Spinal Cord of G93A Mutant hSOD1 Mice Resulting in Disruption of Mitochondrial Glutathione Transport." Biomedicines 11, no. 1 (December 27, 2022): 61. http://dx.doi.org/10.3390/biomedicines11010061.

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Mitochondrial oxidative stress and dysfunction are strongly implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Glutathione (GSH) is an endogenous antioxidant that exists as distinct cytosolic and mitochondrial pools. The status of the mitochondrial GSH pool is reliant on transport from the cytosol through the 2-oxoglutarate carrier (OGC), an inner membrane anion carrier. We have previously reported that the outer mitochondrial membrane protein, Bcl-2, directly binds GSH and is a key regulator of OGC-dependent mitochondrial GSH transport. Here, we show that G93A mutant SOD1 (Cu, Zn-superoxide dismutase) reduces the binding of GSH to Bcl-2 and disrupts mitochondrial GSH uptake in vitro. In the G93A mutant hSOD1 mouse model of ALS, mitochondrial GSH is significantly depleted in spinal cord of end-stage mice. Finally, we show that OGC is heavily S-nitrosylated in the spinal cord of end-stage mice and consequently, the GSH uptake capacity of spinal cord mitochondria isolated from these mutant mice is significantly diminished. Collectively, these findings suggest that spinal cord GSH depletion, particularly at the level of the mitochondria, plays a significant role in ALS pathogenesis induced by mutant SOD1. Furthermore, the depletion of mitochondrial GSH in the G93A mutant hSOD1 mouse model may be caused by the S-nitrosylation of OGC and the capacity of mutant SOD1 to disrupt the Bcl-2/GSH interaction, resulting in a disruption of mitochondrial GSH transport.

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16

Banci, Lucia, Letizia Barbieri, Ivano Bertini, Francesca Cantini, and Enrico Luchinat. "In-cell NMR in E. coli to Monitor Maturation Steps of hSOD1." PLoS ONE 6, no. 8 (August 24, 2011): e23561. http://dx.doi.org/10.1371/journal.pone.0023561.

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17

Iuchi, Yoshihito, Futoshi Okada, Rina Takamiya, Noriko Kibe, Satoshi Tsunoda, Osamu Nakajima, Kazuyo Toyoda, et al. "Rescue of anaemia and autoimmune responses in SOD1-deficient mice by transgenic expression of human SOD1 in erythrocytes." Biochemical Journal 422, no. 2 (August 13, 2009): 313–20. http://dx.doi.org/10.1042/bj20090176.

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Анотація:

Oxidative stress has been implicated as a cause of various diseases such as anaemia. We found that the SOD1 [Cu,Zn-SOD (superoxide dismutase)] gene deficiency causes anaemia, the production of autoantibodies against RBCs (red blood cells) and renal damage. In the present study, to further understand the role of oxidative stress in the autoimmune response triggered by SOD1 deficiency, we generated mice that had the hSOD1 (human SOD1) transgene under regulation of the GATA-1 promoter, and bred the transgene onto the SOD1−/− background (SOD1−/−;hSOD1tg/+). The lifespan of RBCs, levels of intracellular reactive oxygen species, and RBC content in SOD1−/−;hSOD1tg/+ mice, were approximately equivalent to those of SOD1+/+ mice. The production of antibodies against lipid peroxidation products, 4-hydroxy-2-nonenal and acrolein, as well as autoantibodies against RBCs and carbonic anhydrase II were elevated in the SOD1−/− mice, but were suppressed in the SOD1−/−;hSOD1tg/+ mice. Renal function, as judged by blood urea nitrogen, was improved in the transgenic mice. These results rule out the involvement of a defective immune system in the autoimmune response of SOD1-deficient mice, because SOD1−/−;hSOD1tg/+ mice carry the hSOD1 protein only in RBCs. Metabolomic analysis indicated a shift in glucose metabolism to the pentose phosphate pathway and a decrease in the energy charge potential of RBCs in SOD1-deficient mice. We conclude that the increase in reactive oxygen species due to SOD1 deficiency accelerates RBC destruction by affecting carbon metabolism and increasing oxidative modification of lipids and proteins. The resulting oxidation products are antigenic and, consequently, trigger autoantibody production, leading to autoimmune responses.

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18

Scorisa, Juliana Milani, Tatiana Duobles, Gabriela Pintar de Oliveira, Jessica Ruivo Maximino, and Gerson Chadi. "The review of the methods to obtain non-neuronal cells to study glial influence on Amyotrophic Lateral Sclerosis pathophysiology at molecular level in vitro." Acta Cirurgica Brasileira 25, no. 3 (June 2010): 281–89. http://dx.doi.org/10.1590/s0102-86502010000300011.

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Анотація:

PURPOSE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that displays a rapid evolution. Current treatments have failed to revert clinical symptoms because the mechanisms involved in the death of motoneuron are still unknown. Recent publications have put non-neuronal cells, particularly, astrocyte and microglia, in the scenario of pathophisiology of the disease. Animal models for ALS, particularly transgenic mice expressing the human SOD1 gene with a G93A mutation (hSOD1), are available and display the phenotype of the disease at cellular and clinical levels. However, it is a lack of detailed information regarding the methods to study the disease in vitro to better understand the contribution of non-neuronal cells in the onset and progression of the pathology. METHODS: Colonies of Swiss mice and transgenic mice expressing hSOD1 mutation as well as non-transgenic controls (wild-type) were amplified after a genotyping evaluation. Disease progression was followed behaviorally and mortality was registered. Highly purified primary cultures of astrocytes and microglia from mouse spinal cord were obtained. Cells were identified by means of GFAP and CD11B immunocytochemistry. The purity of astroglial and microglial cell cultures was also accompanied by means of Western blot and RT-PCR analyses employing a number of markers. RESULTS: The disease onset was about 105 days and the majority of transgenic mice displayed the disease symptoms by 125 days of age and reached the endpoint 20 days later. A substantial motor weakens was registered in the transgenic mice compared to wild-type at the end point. Immunocytochemical, biochemical and RT-PCR analyses demonstrated a highly purified primary cultures of spinal cord astrocytes and microglia. CONCLUSION: It is possible to achieve highly purified primary cultures of spinal cord astrocytes and microglia to be employed in cellular and molecular analyses of the influence of such non-neuronal cells in the pathophysiology of ALS.

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Peng, Jialing, Jingrui Pan, Jingjing Mo, and Ying Peng. "MPO/HOCl Facilitates Apoptosis and Ferroptosis in the SOD1G93A Motor Neuron of Amyotrophic Lateral Sclerosis." Oxidative Medicine and Cellular Longevity 2022 (February 7, 2022): 1–19. http://dx.doi.org/10.1155/2022/8217663.

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Background. Oxidative stress and reactive oxygen species (ROS) are important in the pathogenesis of amyotrophic lateral sclerosis (ALS). Hypochlorous acid (HOCl) is a powerful oxidant of the reactive oxygen species (ROS) family. HOCl’s role in the progress of ALS remains unclear due to the lack of an effective HOCl detection method. Cumulative evidence supports oxidative damage incurred by mutant hSOD1 contributing to motor neuron death; however, whether HOCl as well as its catalytic enzyme myeloperoxidase (MPO) function in the cell death of SOD1G93A ALS remains elusive. Methods. The hSOD1WT and hSOD1G93A NSC-34 cell and SOD1G93A ALS mouse models were employed. With a novel fluorescent HOCl probe, HKOCl-3, we detected the expressions of HOCl and its catalytic enzyme, MPO, in the above models in vitro and in vivo. The regulation of MPO/HOCl by hSOD1G93A mutation and cell deaths by MPO/HOCl were also assayed, including apoptosis, ferroptosis, and autophagy. Results. Our results showed that hSOD1G93A mutation promoted the activation of the MPO/HOCl pathway in SOD1G93A ALS cell models. The activation of MPO/HOCl pathways facilitated apoptosis and ferroptosis through increasing the Bax/Bcl-2 ratio and expression of caspase-3 or inhibiting the expressions of GPX4 and NQO1 and thus leading to irreversible lipid peroxidation. Overexpressed FSP1, a glutathione-independent suppressor, could ameliorate ferroptosis. In vivo, we demonstrated that the activation of the MPO/HOCl pathway occurred differently in motor neurons of the motor cortices, brain stems, and spinal cords in male and female SOD1G93A transgenic mice. In addition, inhibiting MPO improved the motor performance of SOD1G93A transgenic mice, as demonstrated by the rotarod test. Conclusions. We concluded that aggregation of mutant hSOD1 proteins contributed to activation of the MPO/HOCl pathway, triggering apoptosis and ferroptosis in motor neuronal deaths and exerting impaired motor performance.

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20

Tadić, Vedrana, Ayse Malci, Nadine Goldhammer, Beatrice Stubendorff, Saikata Sengupta, Tino Prell, Silke Keiner, et al. "Sigma 1 receptor activation modifies intracellular calcium exchange in the G93A hSOD1 ALS model." Neuroscience 359 (September 2017): 105–18. http://dx.doi.org/10.1016/j.neuroscience.2017.07.012.

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21

Yan, Lina, Weijing Qi, Yaling Liu, Fuling Zhou, Yafei Wang, Lin Bai, Xiaomeng Zhou, et al. "The Protective Effect of Aromatase on NSC-34 Cells with Stably Expressed hSOD1-G93A." Neuroscience 411 (July 2019): 37–46. http://dx.doi.org/10.1016/j.neuroscience.2019.05.022.

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22

Choi, Chan-Il, Young-Don Lee, Byoung Joo Gwag, Sung Ig Cho, Sung-Soo Kim, and Haeyoung Suh-Kim. "Effects of estrogen on lifespan and motor functions in female hSOD1 G93A transgenic mice." Journal of the Neurological Sciences 268, no. 1-2 (May 2008): 40–47. http://dx.doi.org/10.1016/j.jns.2007.10.024.

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23

Banci, L., I. Bertini, F. Cantini, T. Kozyreva, C. Massagni, P. Palumaa, J. T. Rubino, and K. Zovo. "Human superoxide dismutase 1 (hSOD1) maturation through interaction with human copper chaperone for SOD1 (hCCS)." Proceedings of the National Academy of Sciences 109, no. 34 (August 6, 2012): 13555–60. http://dx.doi.org/10.1073/pnas.1207493109.

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24

Yan, Lina, Yaling Liu, Can Sun, Qian Zheng, Pengli Hao, Jingxu Zhai, and Yuanyuan Liu. "Effects of Ovariectomy in an hSOD1-G93A Transgenic Mouse Model of Amyotrophic Lateral Sclerosis (ALS)." Medical Science Monitor 24 (February 2, 2018): 678–86. http://dx.doi.org/10.12659/msm.908786.

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Habisch, Hans-Jörg, Birgit Schwalenstöcker, Ruth Danzeisen, Oliver Neuhaus, Hans-Peter Hartung, and Albert Ludolph. "Limited effects of glatiramer acetate in the high-copy number hSOD1-G93A mouse model of ALS." Experimental Neurology 206, no. 2 (August 2007): 288–95. http://dx.doi.org/10.1016/j.expneurol.2007.05.007.

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26

Dučić, Tanja, Stefan Stamenković, Barry Lai, Pavle Andjus, and Vladan Lučić. "Multimodal Synchrotron Radiation Microscopy of Intact Astrocytes from the hSOD1 G93A Rat Model of Amyotrophic Lateral Sclerosis." Analytical Chemistry 91, no. 2 (December 20, 2018): 1460–71. http://dx.doi.org/10.1021/acs.analchem.8b04273.

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27

Wang, T. H., S. Y. Wang, X. D. Wang, H. Q. Jiang, Y. Q. Yang, Y. Wang, J. L. Cheng, C. T. Zhang, W. W. Liang, and H. L. Feng. "Fisetin Exerts Antioxidant and Neuroprotective Effects in Multiple Mutant hSOD1 Models of Amyotrophic Lateral Sclerosis by Activating ERK." Neuroscience 379 (May 2018): 152–66. http://dx.doi.org/10.1016/j.neuroscience.2018.03.008.

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28

Koh, Seong-Ho, Young-Bae Lee, Kyung S. Kim, Hyun-Jung Kim, Manho Kim, Young Joo Lee, Juhan Kim, Kwang Woo Lee та Seung Hyun Kim. "Role of GSK-3β activity in motor neuronal cell death induced by G93A or A4V mutant hSOD1 gene". European Journal of Neuroscience 22, № 2 (21 липня 2005): 301–9. http://dx.doi.org/10.1111/j.1460-9568.2005.04191.x.

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Ferreira Queiroz, Raphael, Veronica Paviani, Fernando Rodrigues Coelho, Emerson Finco Marques, Paolo Di Mascio, and Ohara Augusto. "The Carbonylation and Covalent Dimerization of hSOD1 Caused by Its Bicarbonate-Dependent Peroxidase Activity Is Inhibited by Tempol." Free Radical Biology and Medicine 65 (November 2013): S93. http://dx.doi.org/10.1016/j.freeradbiomed.2013.10.621.

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30

Pehar, Mariana, Gyda Beeson, Craig C. Beeson, Jeffrey A. Johnson, and Marcelo R. Vargas. "Mitochondria-Targeted Catalase Reverts the Neurotoxicity of hSOD1G93A Astrocytes without Extending the Survival of ALS-Linked Mutant hSOD1 Mice." PLoS ONE 9, no. 7 (July 23, 2014): e103438. http://dx.doi.org/10.1371/journal.pone.0103438.

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31

Andjus, Pavle, Stefan Stamenković, and Tanja Dučić. "Synchrotron radiation-based FTIR spectro-microscopy of the brainstem of the hSOD1 G93A rat model of amyotrophic lateral sclerosis." European Biophysics Journal 48, no. 5 (June 26, 2019): 475–84. http://dx.doi.org/10.1007/s00249-019-01380-5.

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32

Harlan, Benjamin A., Kelby M. Killoy, Mariana Pehar, Liping Liu, Johan Auwerx, and Marcelo R. Vargas. "Evaluation of the NAD+ biosynthetic pathway in ALS patients and effect of modulating NAD+ levels in hSOD1-linked ALS mouse models." Experimental Neurology 327 (May 2020): 113219. http://dx.doi.org/10.1016/j.expneurol.2020.113219.

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Bastow, Emma L., Campbell W. Gourlay, and Mick F. Tuite. "Using yeast models to probe the molecular basis of amyotrophic lateral sclerosis." Biochemical Society Transactions 39, no. 5 (September 21, 2011): 1482–87. http://dx.doi.org/10.1042/bst0391482.

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Анотація:

ALS (amyotrophic lateral sclerosis) is a fatal neurodegenerative disease attributable to the death of motor neurons. Associated with ALS are mutations in the genes encoding SOD1 (superoxide dismutase 1), FUS (fused in Sarcoma) protein and TDP-43 (TAR DNA-binding protein-43) each of which leads to aggregation of the respective protein. For example, the ALS-associated mutations in the hSOD1 (human SOD1) gene typically destabilize the native SOD homodimer, leading to misfolding, aggregation and degradation of SOD1. The ALS-associated pathology is not a consequence of the functional inactivation of SOD1 itself, but is rather due to a toxic gain-of-function triggered by mutant SOD1. Recently, the molecular basis of a number of human neurodegenerative diseases resulting from protein misfolding and aggregation, including fALS (familial ALS), was probed by using the baker's yeast, Saccharomyces cerevisiae, as a highly tractable model. Such studies have, for example, identified novel mutant SOD1-specific interactions and demonstrated that mutant SOD1 disrupts mitochondrial homoeostasis. Features of ALS associated with TDP-43 aggregation have also been recapitulated in S. cerevisiae including the identification of modulators of the toxicity of TDP-43. In this paper, we review recent studies of ALS pathogenesis using S. cerevisiae as a model organism and summarize the potential mechanisms involved in ALS progression.

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Fritz, Elsa, Pamela Izaurieta, Alexandra Weiss, Franco R. Mir, Patricio Rojas, David Gonzalez, Fabiola Rojas, Robert H. Brown, Rodolfo Madrid, and Brigitte van Zundert. "Mutant SOD1-expressing astrocytes release toxic factors that trigger motoneuron death by inducing hyperexcitability." Journal of Neurophysiology 109, no. 11 (June 1, 2013): 2803–14. http://dx.doi.org/10.1152/jn.00500.2012.

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Анотація:

Amyotrophic lateral sclerosis (ALS) is a devastating paralytic disorder caused by dysfunction and degeneration of motoneurons starting in adulthood. Recent studies using cell or animal models document that astrocytes expressing disease-causing mutations of human superoxide dismutase 1 (hSOD1) contribute to the pathogenesis of ALS by releasing a neurotoxic factor(s). Neither the mechanism by which this neurotoxic factor induces motoneuron death nor its cellular site of action has been elucidated. Here we show that acute exposure of primary wild-type spinal cord cultures to conditioned medium derived from astrocytes expressing mutant SOD1 (ACM-hSOD1G93A) increases persistent sodium inward currents (PCNa), repetitive firing, and intracellular calcium transients, leading to specific motoneuron death days later. In contrast to TTX, which paradoxically increased twofold the amplitude of calcium transients and killed motoneurons, reduction of hyperexcitability by other specific (mexiletine) and nonspecific (spermidine and riluzole) blockers of voltage-sensitive sodium (Nav) channels restored basal calcium transients and prevented motoneuron death induced by ACM-hSOD1G93A. These findings suggest that riluzole, the only FDA-approved drug with known benefits for ALS patients, acts by inhibiting hyperexcitability. Together, our data document that a critical element mediating the non-cell-autonomous toxicity of ACM-hSOD1G93A on motoneurons is increased excitability, an observation with direct implications for therapy of ALS.

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35

Vargas, Marcelo R., Neal C. Burton, Li Gan, Delinda A. Johnson, Matthias Schäfer, Sabine Werner, and Jeffrey A. Johnson. "Absence of Nrf2 or Its Selective Overexpression in Neurons and Muscle Does Not Affect Survival in ALS-Linked Mutant hSOD1 Mouse Models." PLoS ONE 8, no. 2 (February 13, 2013): e56625. http://dx.doi.org/10.1371/journal.pone.0056625.

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36

Peggion, Caterina, Valeria Scalcon, Maria Lina Massimino, Kelly Nies, Raffaele Lopreiato, Maria Pia Rigobello, and Alessandro Bertoli. "SOD1 in ALS: Taking Stock in Pathogenic Mechanisms and the Role of Glial and Muscle Cells." Antioxidants 11, no. 4 (March 23, 2022): 614. http://dx.doi.org/10.3390/antiox11040614.

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Анотація:

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the loss of motor neurons in the brain and spinal cord. While the exact causes of ALS are still unclear, the discovery that familial cases of ALS are related to mutations in the Cu/Zn superoxide dismutase (SOD1), a key antioxidant enzyme protecting cells from the deleterious effects of superoxide radicals, suggested that alterations in SOD1 functionality and/or aberrant SOD1 aggregation strongly contribute to ALS pathogenesis. A new scenario was opened in which, thanks to the generation of SOD1 related models, different mechanisms crucial for ALS progression were identified. These include excitotoxicity, oxidative stress, mitochondrial dysfunctions, and non-cell autonomous toxicity, also implicating altered Ca2+ metabolism. While most of the literature considers motor neurons as primary target of SOD1-mediated effects, here we mainly discuss the effects of SOD1 mutations in non-neuronal cells, such as glial and skeletal muscle cells, in ALS. Attention is given to the altered redox balance and Ca2+ homeostasis, two processes that are strictly related with each other. We also provide original data obtained in primary myocytes derived from hSOD1(G93A) transgenic mice, showing perturbed expression of Ca2+ transporters that may be responsible for altered mitochondrial Ca2+ fluxes. ALS-related SOD1 mutants are also responsible for early alterations of fundamental biological processes in skeletal myocytes that may impinge on skeletal muscle functions and the cross-talk between muscle cells and motor neurons during disease progression.

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Cai, Mudan, and Eun Jin Yang. "Ginsenoside Re Attenuates Neuroinflammation in a Symptomatic ALS Animal Model." American Journal of Chinese Medicine 44, no. 02 (January 2016): 401–13. http://dx.doi.org/10.1142/s0192415x16500233.

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive loss of upper and lower motor neurons, which cause paralysis and respiratory dysfunction. There is currently no permanently effective drug for patients with ALS. Ginsenoside Re (G-Re), one of the most active ingredients of ginseng, has pharmacological activities that affect a number of targets. To investigate the effects of G-Re on neuroinflammation, we used G-Re (2.5[Formula: see text][Formula: see text]g/g) at the Joksamni acupressure point (ST36) once every other day for one week. To evaluate G-Re function in symptomatic human-superoxide dismutase 1 (hSOD1[Formula: see text] transgenic mice, immunohistochemistry and Western blot analysis were performed with the spinal cord of symptomatic hSOD1G93A transgenic mice. Here, we report that G-Re exhibits potent neuroprotective effects against neuroinflammation in a murine model of ALS. G-Re treatment reduced the loss of motor neurons and active-microglia-related expression of Iba-1 in the spinal cord of symptomatic hSOD1G93A transgenic mice. In addition, compared with age-matched hSOD1G93A mice, G-Re-treated hSOD1G93A mice showed a significant reduction in expression of pro-inflammatory proteins such as CD14 and TNF-[Formula: see text] protein related to TLR4 signaling pathway. G-Re administration also led to a decrease in cell death-related phospho-p38 protein levels, and had an antioxidative effect by reducing HO1 expression. Together, our data suggest that G-Re could have potent anti-neuroinflammatory effects on ALS by inhibiting the TLR4 pathway.

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Choudhury, Sourav, Lorelei Stoica, Anne F. Harris, Damien Cabral, Heather L. Gray-Edwards, Jacob A. Johnson, Aime K. Johnson, Douglas R. Martin, and Miguel Sena-Esteves. "263. A Novel Peptide-Grafted AAV Capsid Exhibits Enhanced CNS Transduction in Both Adult Mice and Cat, as Well as SOD1 Knockdown in Adult hSOD1 ALS Mice." Molecular Therapy 23 (May 2015): S105. http://dx.doi.org/10.1016/s1525-0016(16)33872-2.

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39

Zhang, Chunting, Yueqing Yang, Weiwei Liang, Tianhang Wang, Shuyu Wang, Xudong Wang, Ying Wang, Hongquan Jiang та Honglin Feng. "Neuroprotection by urate on the mutant hSOD1-related cellular and Drosophila models of amyotrophic lateral sclerosis: Implication for GSH synthesis via activating Akt/GSK3β/Nrf2/GCLC pathways". Brain Research Bulletin 146 (березень 2019): 287–301. http://dx.doi.org/10.1016/j.brainresbull.2019.01.019.

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40

Wang, Jing, Yun Zhang, Lu Tang, Nan Zhang, and Dongsheng Fan. "Protective effects of resveratrol through the up-regulation of SIRT1 expression in the mutant hSOD1-G93A-bearing motor neuron-like cell culture model of amyotrophic lateral sclerosis." Neuroscience Letters 503, no. 3 (October 2011): 250–55. http://dx.doi.org/10.1016/j.neulet.2011.08.047.

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41

Ramirez, Dario C., Sandra E. Gomez-Mejiba, Jean T. Corbett, Leesa J. Deterding, Kenneth B. Tomer, and Ronald P. Mason. "Cu,Zn-superoxide dismutase-driven free radical modifications: copper- and carbonate radical anion-initiated protein radical chemistry." Biochemical Journal 417, no. 1 (December 12, 2008): 341–53. http://dx.doi.org/10.1042/bj20070722.

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Анотація:

The understanding of the mechanism, oxidant(s) involved and how and what protein radicals are produced during the reaction of wild-type SOD1 (Cu,Zn-superoxide dismutase) with H2O2 and their fate is incomplete, but a better understanding of the role of this reaction is needed. We have used immuno-spin trapping and MS analysis to study the protein oxidations driven by human (h) and bovine (b) SOD1 when reacting with H2O2 using HSA (human serum albumin) and mBH (mouse brain homogenate) as target models. In order to gain mechanistic information about this reaction, we considered both copper- and CO3•− (carbonate radical anion)-initiated protein oxidation. We chose experimental conditions that clearly separated SOD1-driven oxidation via CO3•− from that initiated by copper released from the SOD1 active site. In the absence of (bi)carbonate, site-specific radical-mediated fragmentation is produced by SOD1 active-site copper. In the presence of (bi)carbonate and DTPA (diethylenetriaminepenta-acetic acid) (to suppress copper chemistry), CO3•− produced distinct radical sites in both SOD1 and HSA, which caused protein aggregation without causing protein fragmentation. The CO3•− produced by the reaction of hSOD1 with H2O2 also produced distinctive DMPO (5,5-dimethylpyrroline-N-oxide) nitrone adduct-positive protein bands in the mBH. Finally, we propose a biochemical mechanism to explain CO3•− production from CO2, enhanced protein radical formation and protection by (bi)carbonate against H2O2-induced fragmentation of the SOD1 active site. Our present study is important for establishing experimental conditions for studying the molecular mechanism and targets of oxidation during the reverse reaction of SOD1 with H2O2; these results are the first step in analysing the critical targets of SOD1-driven oxidation during pathological processes such as neuroinflammation.

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42

Stankiewicz, Trisha R., Claudia Pena, Ron J. Bouchard, and Daniel A. Linseman. "Dysregulation of Rac or Rho elicits death of motor neurons and activation of these GTPases is altered in the G93A mutant hSOD1 mouse model of amyotrophic lateral sclerosis." Neurobiology of Disease 136 (March 2020): 104743. http://dx.doi.org/10.1016/j.nbd.2020.104743.

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Wang, Tianhang, Jiling Cheng, Shuyu Wang, Xudong Wang, Hongquan Jiang, Yueqing Yang, Ying Wang, Chunting Zhang, Weiwei Liang та Honglin Feng. "α-Lipoic acid attenuates oxidative stress and neurotoxicity via the ERK/Akt-dependent pathway in the mutant hSOD1 related Drosophila model and the NSC34 cell line of amyotrophic lateral sclerosis". Brain Research Bulletin 140 (червень 2018): 299–310. http://dx.doi.org/10.1016/j.brainresbull.2018.05.019.

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Zarich, Natasha, José Luis Oliva, Natalia Martínez, Rocío Jorge, Alicia Ballester, Silvia Gutiérrez-Eisman, Susana García-Vargas, and José M. Rojas. "Grb2 Is a Negative Modulator of the Intrinsic Ras-GEF Activity of hSos1." Molecular Biology of the Cell 17, no. 8 (August 2006): 3591–97. http://dx.doi.org/10.1091/mbc.e05-12-1104.

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Анотація:

hSos1 is a Ras guanine-nucleotide exchange factor. It was suggested that the carboxyl-terminal region of hSos1 down-regulates hSos1 functionality and that the intrinsic guanine-nucleotide exchange activity of this protein may be different before and after stimulation of tyrosine kinase receptors. Using different myristoylated hSos1 full-length and carboxyl-terminal truncated mutants, we show that Grb2 function accounts not only for recruitment of hSos1 to the plasma membrane but also for modulation of hSos1 activity. Our results demonstrate that the first two canonical Grb2 binding sites, inside the carboxyl-terminal region of hSos1, are responsible for this regulation. Following different approaches, such as displacement of Grb2 from the hSos1-Grb2 complex or depletion of Grb2 levels by small interfering RNA, we found that the full-length Grb2 proteins mediate negative regulation of the intrinsic Ras guanine-nucleotide exchange activity of hSos1.

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45

Wang, Shanshan, Taiga Ichinomiya, Paul Savchenko, Dongsheng Wang, Atsushi Sawada, Xiaojing Li, Tiffany Duong, et al. "Subpial delivery of adeno-associated virus 9-synapsin-caveolin-1 (AAV9-SynCav1) preserves motor neuron and neuromuscular junction morphology, motor function, delays disease onset, and extends survival in hSOD1^G93A mice." Theranostics 12, no. 12 (2022): 5389–403. http://dx.doi.org/10.7150/thno.72614.

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Yin, Xiang, Shuyu Wang, Yan Qi, Xudong Wang, Hongquan Jiang, Tianhang Wang, Yueqing Yang, Ying Wang, Chunting Zhang та Honglin Feng. "Astrocyte elevated gene-1 is a novel regulator of astrogliosis and excitatory amino acid transporter-2 via interplaying with nuclear factor-κB signaling in astrocytes from amyotrophic lateral sclerosis mouse model with hSOD1 G93A mutation". Molecular and Cellular Neuroscience 90 (липень 2018): 1–11. http://dx.doi.org/10.1016/j.mcn.2018.05.004.

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Goursaud, Stéphanie, Marylène C. Focant, Julie V. Berger, Yannick Nizet, Jean‐Marie Maloteaux, and Emmanuel Hermans. "The VPAC 2 agonist peptide histidine isoleucine (PHI) up‐regulates glutamate transport in the corpus callosum of a rat model of amyotrophic lateral sclerosis (hSOD1 G93A ) by inhibiting caspase‐3 mediated inactivation of GLT‐1a." FASEB Journal 25, no. 10 (July 5, 2011): 3674–86. http://dx.doi.org/10.1096/fj.11-182337.

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48

Stankiewicz, Trisha R., Claudia Pena, Ron J. Bouchard, and Daniel A. Linseman. "Corrigendum to “Dysregulation of Rac or Rho elicits death of motor neurons and activation of these GTPases is altered in the G93A mutant hSOD1 mouse model of amyotrophic lateral sclerosis” [Neurobiology of Disease 136 (2020) 104743]." Neurobiology of Disease 144 (October 2020): 105023. http://dx.doi.org/10.1016/j.nbd.2020.105023.

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49

Chen, Harn-Shen, Tzu-En Wu, Chi-Chang Juan, and Hong-Da Lin. "Myocardial heat shock protein 60 expression in insulin-resistant and diabetic rats." Journal of Endocrinology 200, no. 2 (October 22, 2008): 151–57. http://dx.doi.org/10.1677/joe-08-0387.

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Анотація:

Heat shock protein 60 (HSPD1) plays a critical role in myocardial protection. Its reduced expression may lower myocardial protection against ischemic injury in the diabetic state. This study was conducted to investigate the natural course of fructose-fed insulin-resistant rats, define changes in myocardial HSPD1 expression, and determine the effects of thiazolidinedione or anti-hypertensive treatment. Results showed that insulin resistance with hyperinsulinemia and hypertension developed after 6 weeks of fructose feeding. This time-course study also showed that myocardial HSPD1 expression was mildly increased in week 6 (P=0.05) and significantly increased in week 8. Rosiglitazone-treated rats had restored systolic blood pressure (BP) and normalized plasma insulin level during oral glucose tolerance tests, whereas amlodipine-treated rats restored only systolic BP. Both amlodipine and rosiglitazone treatments normalized the abundance of myocardial HSPD1 expression in fructose-fed rats. When these rats received streptozotocin injection and diabetes developed, myocardial HSPD1 expression decreased despite persistent hypertension. In conclusion, this is the first study to report that myocardial HSPD1 expression is increased in high-fructose-fed rats, which may be due to increased BP. Once the high-fructose-fed rats developed diabetes with insulin deficiency, the myocardial HSPD1 expression decreased in spite of persistent hypertension.

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Coutinho, Agnes E., Tiina M. J. Kipari, Zhenguang Zhang, Cristina L. Esteves, Christopher D. Lucas, James S. Gilmour, Scott P. Webster та ін. "11β-Hydroxysteroid Dehydrogenase Type 1 Is Expressed in Neutrophils and Restrains an Inflammatory Response in Male Mice". Endocrinology 157, № 7 (1 липня 2016): 2928–36. http://dx.doi.org/10.1210/en.2016-1118.

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Endogenous glucocorticoid action within cells is enhanced by prereceptor metabolism by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which converts intrinsically inert cortisone and 11-dehydrocorticosterone into active cortisol and corticosterone, respectively. 11β-HSD1 is highly expressed in immune cells elicited to the mouse peritoneum during thioglycollate-induced peritonitis and is down-regulated as the inflammation resolves. During inflammation, 11β-HSD1-deficient mice show enhanced recruitment of inflammatory cells and delayed acquisition of macrophage phagocytic capacity. However, the key cells in which 11β-HSD1 exerts these effects remain unknown. Here we have identified neutrophils (CD11b+,Ly6G+,7/4+ cells) as the thioglycollate-recruited cells that most highly express 11β-HSD1 and show dynamic regulation of 11β-HSD1 in these cells during an inflammatory response. Flow cytometry showed high expression of 11β-HSD1 in peritoneal neutrophils early during inflammation, declining at later states. In contrast, expression in blood neutrophils continued to increase during inflammation. Ablation of monocytes/macrophages by treatment of CD11b-diphtheria-toxin receptor transgenic mice with diphtheria toxin prior to thioglycollate injection had no significant effect on 11β-HSD1 activity in peritoneal cells, consistent with neutrophils being the predominant 11β-HSD1 expressing cell type at this time. Similar to genetic deficiency in 11β-HSD1, acute inhibition of 11β-HSD1 activity during thioglycollate-induced peritonitis augmented inflammatory cell recruitment to the peritoneum. These data suggest that neutrophil 11β-HSD1 increases during inflammation to contribute to the restraining effect of glucocorticoids upon neutrophil-mediated inflammation. In human neutrophils, lipopolysaccharide activation increased 11β-HSD1 expression, suggesting the antiinflammatory effects of 11β-HSD1 in neutrophils may be conserved in humans.

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