Oxidative stress promotes mutant huntingtin aggregation and mutant huntingtin-dependent cell death by mimicking proteasomal malfunction

Goswami, Anand; Dikshit, Priyanka; Mishra, Amit; Mulherkar, Shalaka; Nukina, Nobuyuki; Jana, Nihar Ranjan

doi:10.1016/j.bbrc.2006.01.136

Cited by 108 publications

(70 citation statements)

References 27 publications

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“…7 demonstrate that hypertonicity causes protein aggregation much more rapidly than inhibition of lysosomal and proteasomal function. This conclusion is supported by studies in cultured mammalian cells, which demonstrate that protein aggregation is induced only after prolonged inhibition of proteasome degradation (3,20). Although we cannot completely rule out the possibility that compromised protein degradation contributes to protein aggregation during hypertonic stress, our results indicate that other more rapidly acting mechanisms, such as macromolecular crowding (16), induce aggregation in hypertonically stressed cells.…”

Section: Resultssupporting

confidence: 75%

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Genome-wide RNAi screen and in vivo protein aggregation reporters identify degradation of damaged proteins as an essential hypertonic stress response

Choe¹,

Strange²

2008

American Journal of Physiology-Cell Physiology

100

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Choe KP, Strange K. Genome-wide RNAi screen and in vivo protein aggregation reporters identify degradation of damaged proteins as an essential hypertonic stress response. Am J Physiol Cell Physiol 295: C1488 -C1498, 2008. First published October 1, 2008 doi:10.1152/ajpcell.00450.2008.-The damaging effects of hypertonic stress on cellular proteins are poorly defined, and almost nothing is known about the pathways that detect and repair hypertonicityinduced protein damage. To begin addressing these problems, we screened ϳ19,000 Caenorhabditis elegans genes by RNA interference (RNAi) feeding and identified 40 that are essential for survival during acute hypertonic stress. Half (20 of 40) of these genes encode proteins that function to detect, transport, and degrade damaged proteins, including components of the ubiquitin-proteasome system, endosomal sorting complexes, and lysosomes. High-molecular-weight ubiquitin conjugates increase during hypertonic stress, suggesting a global change in the ubiquitinylation state of endogenous proteins. Using a polyglutamine-containing fluorescent reporter, we demonstrate that cell shrinkage induces rapid protein aggregation in vivo and that many of the genes that are essential for survival during hypertonic stress function to prevent accumulation of aggregated proteins. High levels of urea, a strong protein denaturant, do not cause aggregation, suggesting that factors such as macromolecular crowding also contribute to protein aggregate formation during cell shrinkage. Acclimation of C. elegans to mild hypertonicity dramatically increases the osmotic threshold for protein aggregation, demonstrating that protein aggregation-inhibiting pathways are activated by osmotic stress. Our studies demonstrate that hypertonic stress induces protein damage in vivo and that detection and degradation of damaged proteins are essential mechanisms for survival under hypertonic conditions.

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Section: Resultssupporting

confidence: 75%

“…Oxidative stress promotes aggregation of polyglutaminecontaining proteins (20). Exposure to hypertonic medium elevates reactive oxygen species in cultured mammalian cells (32,63).…”

Section: Resultsmentioning

confidence: 99%

Genome-wide RNAi screen and in vivo protein aggregation reporters identify degradation of damaged proteins as an essential hypertonic stress response

Choe¹,

Strange²

2008

American Journal of Physiology-Cell Physiology

100

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“…Goat anti-rabbit IgG-fluorescein isothiocyanate was purchased from Vector laboratories, and horseradish peroxidase-conjugated anti-mouse and anti-rabbit IgG were from Amersham Biosciences. The source of plasmids ubiquitin (with HA tag), pd1EGFP-N1, Hsp70, and Hsp40 are described elsewhere (29,35). IB-␣-EGFP plasmid was purchased from BD Biosciences.…”

Section: Methodsmentioning

confidence: 99%

Biochemical Characterization of Glutaredoxins from Chlamydomonas reinhardtii Reveals the Unique Properties of a Chloroplastic CGFS-type Glutaredoxin

Zaffagnini

Michelet

Massot

et al. 2008

Journal of Biological Chemistry

128

171

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Aspirin and other nonsteroidal anti-inflammatory drugs inhibit cell proliferation and induce apoptosis in various cancer cell lines, which is considered to be an important mechanism for their anti-tumor activity and prevention of carcinogenesis. However, the molecular mechanisms through which these compounds induce apoptosis are not well understood. Here we have found that aspirin treatment of the mouse Neuro 2a cells impaired the proteasome function and caused severe mitochondrial abnormalities. Treatment with aspirin lead to a dose-and time-dependent decrease in proteasome activity and an increase in the accumulation of ubiquitylated proteins in the cells, which correlated with its effect on cell death. Aspirin exposure also resulted in an increase in the half-life of pd1EGFP, a model substrate of proteasome, as well as various intracellular substrates like Bax, IB-␣, p53, and p27 kip1 . Aspirin-induced proteasomal malfunction might be responsible, at least in part, for the downregulation of NF-B activity and neurite outgrowth. Finally, we have shown that aspirin treatment caused changes in the mitochondrial membrane potential, release of cytochrome c from mitochondria, and activation of caspase-9 and -3, which could be because of the proteasomal dysfunction.

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“…Oxidative stress is one of several dysfunctional mechanisms described in HD [4][5][6][7][8], which may result from impaired mitochondrial function, namely due to interaction of the organelle with mHtt [9] and/or imbalanced levels of antioxidants.…”

Section: Introductionmentioning

confidence: 99%

Glutathione redox cycle dysregulation in Huntington’s disease knock-in striatal cells

Ribeiro

Rosenstock

Cunha‐Oliveira

et al. 2012

Free Radical Biology and Medicine

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a b s t r a c tHuntington's disease (HD) is a CAG repeat disorder affecting the HD gene, which encodes for huntingtin (Htt) and is characterized by prominent cell death in the striatum. Oxidative stress was previously implicated in HD neurodegeneration, but the role of the major endogenous antioxidant system, the glutathione redox cycle, has been less studied following expression of full-length mutant Htt (FL-mHtt). Thus, in this work we analyzed the glutathione system in striatal cells derived from HD knock-in mice expressing mutant Htt versus wild-type cells. Mutant cells showed increased intracellular reactive oxygen species (ROS) and caspase-3 activity, which were significantly prevented following treatment with glutathione ethyl ester. Interestingly, mutant cells exhibited an increase in intracellular levels of both reduced and oxidized forms of glutathione, and enhanced activities of glutathione peroxidase (GPx) and glutathione reductase (GRed). Furthermore, glutathione-S-transferase (GST) and g-glutamyl transpeptidase (g-GT) activities were also increased in mutant cells. Nevertheless, glutamate-cysteine ligase (GCL) and glutathione synthetase (GS) activities and levels of GCL catalytic subunit were decreased in cells expressing FL-mHtt, highly suggesting decreased de novo synthesis of glutathione. Enhanced intracellular total glutathione, despite decreased synthesis, could be explained by decreased extracellular glutathione in mutant cells. This occurred concomitantly with decreased mRNA expression levels and activity of the multidrug resistance protein 1 (Mrp1), a transport protein that mediates cellular export of glutathione disulfide and glutathione conjugates. Additionally, inhibition of Mrp1 enhanced intracellular GSH in wild-type cells only. These data suggest that FL-mHtt affects the export of glutathione by decreasing the expression of Mrp1. Data further suggest that boosting of GSH-related antioxidant defense mechanisms induced by FL-mHtt is insufficient to counterbalance increased ROS formation and emergent apoptotic features in HD striatal cells.

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Oxidative stress promotes mutant huntingtin aggregation and mutant huntingtin-dependent cell death by mimicking proteasomal malfunction

Cited by 108 publications

References 27 publications

Genome-wide RNAi screen and in vivo protein aggregation reporters identify degradation of damaged proteins as an essential hypertonic stress response

Genome-wide RNAi screen and in vivo protein aggregation reporters identify degradation of damaged proteins as an essential hypertonic stress response

Biochemical Characterization of Glutaredoxins from Chlamydomonas reinhardtii Reveals the Unique Properties of a Chloroplastic CGFS-type Glutaredoxin

Glutathione redox cycle dysregulation in Huntington’s disease knock-in striatal cells

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