Induction of multiple heat shock proteins and neuroprotection in a primary culture model of familial amyotrophic lateral sclerosis

Batulan, Zarah; Taylor, David; Aarons, R. J.; Minotti, Sandra; Doroudchi, Mohammad M.; Nalbantoglu, Joséphine; Durham, Heather D.

doi:10.1016/j.nbd.2006.06.017

Cited by 105 publications

(113 citation statements)

References 88 publications

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“…Although there is controversy over the relationship between the aggregation of mutant SOD-1 and disease-related toxicity (reviewed in Ref. 41), only treatments that reduce the formation of cytoplasmic mutant SOD-1 inclusions also prolong survival in the primary motor neuron culture model used in the present study (29,30,(42)(43)(44)(45). This culture system has the distinct advantage of utilizing primary motor neurons, cells with particular vulnerability to mutant SOD-1 toxicity and ALS generally (46,47).…”

Section: Discussionmentioning

confidence: 94%

Tryptophan 32 Potentiates Aggregation and Cytotoxicity of a Copper/Zinc Superoxide Dismutase Mutant Associated with Familial Amyotrophic Lateral Sclerosis

Taylor

Gibbs

Kabashi

et al. 2007

Journal of Biological Chemistry

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One familial form of the neurodegenerative disease, amyotrophic lateral sclerosis, is caused by gain-of-function mutations in the gene encoding copper/zinc superoxide dismutase (SOD-1). This study provides in vivo evidence that normally occurring oxidative modification to SOD-1 promotes aggregation and toxicity of mutant proteins. The oxidation of Trp-32 was identified as a normal modification being present in both wild-type enzyme and SOD-1 with the disease-causing mutation, G93A, isolated from erythrocytes. Mutating Trp-32 to a residue with a slower rate of oxidative modification, phenylalanine, decreased both the cytotoxicity of mutant SOD-1 and its propensity to form cytoplasmic inclusions in motor neurons of dissociated mouse spinal cord cultures. Amyotrophic lateral sclerosis (ALS)5 is an adult onset neurodegenerative disease in which two percent of all cases are caused by mutations in the gene encoding copper/zinc superoxide dismutase (SOD-1) (1). More than 100 mutations distributed throughout the structure of the protein introduce a toxic gain of function that decreases protein solubility, leading to aggregation and the formation of both detergent-insoluble SOD-1 (2, 3) and inclusions that are a histopathological hallmark of ALS (4 -8).The nature of the toxic gain of function imparted by familial ALS (fALS)-causing SOD-1 mutations is not completely understood (reviewed in Ref. 9). These mutations do, however, provide evidence that diverse and relatively minor changes in SOD-1 primary structure can cause fALS. Approximately ninety percent of ALS is sporadic, and it is plausible that posttranslational modification of wild-type proteins affects structural changes analogous to those caused by point mutation (10). Indeed, Lewy body-like inclusions in sporadic ALS are immunoreactive with antibodies to SOD-1 (11-13). It has also been demonstrated that oxidative post-translational modification of SOD-1 occurs in vivo with aging (14) and in association with the fALS (7, 15-17), Parkinson (18), and Alzheimer (18) neurodegenerative diseases. There is also considerable evidence that fALS-causing mutations predispose SOD-1 to post-translational modifications (19 -21), and that in vitro oxidative modification of SOD-1 induces aggregation (22-24).An understanding of how modifications that occur in vivo confer or potentiate toxic properties in proteins is lacking. Given the potential importance of post-translational modification of SOD-1, a study was designed to comprehensively characterize modifications that occur in vivo. Modification-prone residues in wild-type SOD-1 isolated from murine and human erythrocytes were identified and changed to residues that were less likely to be modified. Effects upon survival and aggregation were measured to determine whether preventing modification would attenuate the toxicity of SOD-1 with fALS-causing SOD-1 mutations. Tryptophan 32 (Trp-32) was shown to be modified in a significant fraction of as-isolated SOD-1. Herein we report that changing Trp-32 to a residue with a slower rate ...

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Section: Discussionmentioning

confidence: 94%

Tryptophan 32 Potentiates Aggregation and Cytotoxicity of a Copper/Zinc Superoxide Dismutase Mutant Associated with Familial Amyotrophic Lateral Sclerosis

Taylor

Gibbs

Kabashi

et al. 2007

Journal of Biological Chemistry

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“…These activities involve the inhibition of Apaf-1 oligomerization and caspase activation (95). Motor neurons have a high threshold for the activation of the heat shock response, which is regulated by HSP90 (96). In addition, exogenous addition of HSP70 prevents motor neuron apoptosis induced by trophic factor deprivation (97), suggesting that alterations in HSP90 function by nitration may be responsible for motor neuron death.…”

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confidence: 99%

Prevention of Peroxynitrite-induced Apoptosis of Motor Neurons and PC12 Cells by Tyrosine-containing Peptides

Quijano

Robinson

et al. 2007

Journal of Biological Chemistry

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Although peroxynitrite stimulates apoptosis in many cell types, whether peroxynitrite acts directly as an oxidant or the induction of apoptosis is because of the radicals derived from peroxynitrite decomposition remains unknown. Before undergoing apoptosis because of trophic factor deprivation, primary motor neuron cultures become immunoreactive for nitrotyrosine. We show here using tyrosine-containing peptides that free radical processes mediated by peroxynitrite decomposition products were required for triggering apoptosis in primary motor neurons and in PC12 cells cultures. The same concentrations of tyrosine-containing peptides required to prevent the nitration and apoptosis of motor neurons induced by trophic factor deprivation and of PC12 cells induced by peroxynitrite also prevented peroxynitrite-mediated nitration of motor neurons, brain homogenates, and PC12 cells. The heat shock protein 90 chaperone was nitrated in both trophic factor-deprived motor neurons and PC12 cells incubated with peroxynitrite. Tyrosine-containing peptides did not affect the induction of PC12 cell death by hydrogen peroxide. Tyrosine-containing peptides should protect by scavenging peroxynitrite-derived radicals and not by direct reactions with peroxynitrite as they neither increase the rate of peroxynitrite decomposition nor decrease the bimolecular peroxynitrite-mediated oxidation of thiols. These results reveal an important role for free radicalmediated nitration of tyrosine residues, in apoptosis induced by endogenously produced and exogenously added peroxynitrite; moreover, tyrosine-containing peptides may offer a novel strategy to neutralize the toxic effects of peroxynitrite.

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“…Functional activities of Hsps, such as protein refolding (Fan et al 2003;Goloubinoff and De Los Rios 2007;Mayer 2013;Mattoo and Goloubinoff 2014;Dekker et al 2015) and disruption of protein aggregates (Nillegoda and Bukau 2015;, require co-operation between several different classes of Hsps. Therefore, upregulation of a set of Hsps by activation of heat shock transcription factor 1 (HSF1), the master regulator of heat shock gene transcription, is more effective than genetic manipulation of individual Hsps (Liu et al 2005;Batulan et al 2006;Asea and Brown 2008).…”

Section: Introductionmentioning

confidence: 99%

Induction of heat shock proteins in differentiated human neuronal cells following co-application of celastrol and arimoclomol

Deane

Brown

2016

Cell Stress and Chaperones

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Induction of multiple heat shock proteins and neuroprotection in a primary culture model of familial amyotrophic lateral sclerosis

Cited by 105 publications

References 88 publications

Tryptophan 32 Potentiates Aggregation and Cytotoxicity of a Copper/Zinc Superoxide Dismutase Mutant Associated with Familial Amyotrophic Lateral Sclerosis

Tryptophan 32 Potentiates Aggregation and Cytotoxicity of a Copper/Zinc Superoxide Dismutase Mutant Associated with Familial Amyotrophic Lateral Sclerosis

Prevention of Peroxynitrite-induced Apoptosis of Motor Neurons and PC12 Cells by Tyrosine-containing Peptides

Induction of heat shock proteins in differentiated human neuronal cells following co-application of celastrol and arimoclomol

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