Inhibitors of Cytochrome<i>c</i>Release with Therapeutic Potential for Huntington's Disease

Wang, Xin; Zhu, Shan; Pei, Zhijuan; Drozda, Martin; Stavrovskaya, Irina G.; Signore, Steven J. Del; Cormier, Kerry; Shimony, Ethan M.; Wang, Hongyan; Ferrante, Robert J.; Kristal, Bruce S.; Friedlander, Robert M.

doi:10.1523/jneurosci.1867-08.2008

Cited by 102 publications

(127 citation statements)

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“…Apoptotic neuronal death in HD may therefore be restricted to those areas of the brain that fail to sufficiently upregulate Hsp70, underlining the characteristic neuronal vulnerability of the striatum, perhaps aided by calcium perturbations induced by excitotoxicity (Zeron et al, 2004;Tang et al, 2005). Because Q97-expressing SCG neurons released cytochrome c before death, studies reporting the protective effect of caspase inhibition or suppression of cytochrome c release in HD transgenic mice may reflect the benefit of preserving vulnerable neurons before the onset of death that proceeds by nonapoptotic mechanisms (Ona et al, 1999;Chen et al, 2000;Wang et al, 2008). Recently it was shown that Hsp70 overexpression and reduction of soluble input operate via separate mechanisms in an HD model and both are crucial for neuronal rescue (McLear et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…Whereas some studies indicate the importance of apoptosis Martindale et al, 1998;Saudou et al, 1998;Sanchez et al, 1999;Jana et al, 2001;Tang et al, 2005), others have questioned this conclusion (Jackson et al, 1998;Vonsattel and DiFiglia, 1998;Moulder et al, 1999;Turmaine et al, 2000). Although death may proceed nonapoptotically, components of apoptosis, such as p53-activation, cytochrome c (cyt c) release, and even caspases, may still contribute to HD pathology without full-blown expression of apoptosis being evident (Ona et al, 1999;Chen et al, 2000;Jana et al, 2001;Bae et al, 2005;Wang et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Cytoplasmic Inclusions of Htt Exon1 Containing an Expanded Polyglutamine Tract Suppress Execution of Apoptosis in Sympathetic Neurons

King¹,

Goemans²,

Hafiz³

et al. 2008

J. Neurosci.

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Proteins containing extended polyglutamine repeats cause at least nine neurodegenerative disorders, but the mechanisms of diseaserelated neuronal death remain uncertain. We show that sympathetic neurons containing cytoplasmic inclusions formed by 97 glutamines expressed within human huntingtin exon1-enhanced green fluorescent protein (Q97) undergo a protracted form of nonapoptotic death that is insensitive to Bax deletion or caspase inhibition but is characterized by mitochondrial dysfunction. By treating the neurons with combined cytosine arabinoside and NGF withdrawal, we demonstrate that Q97 confers a powerful resistance to apoptosis at multiple levels: despite normal proapoptotic signaling (elevation of P-ser15-p53 and BimEL), there is no increase of Puma mRNA or Bax activation, both necessary for apoptosis. Even restoration of Bax translocation with overexpressed Puma does not activate apoptosis. We demonstrate that this robust inhibition of apoptosis is caused by Q97-mediated accumulation of Hsp70, which occurs through inhibition of proteasomal activity. Thus, apoptosis is reinstated by short hairpin RNA-mediated knockdown of Hsp70. These findings explain the rarity of apoptotic death in Q97-expressing neurons. Given the proteasomal blockade, we test whether enhancing lysosomal-mediated degradation with rapamycin reduces Q97 accumulation. Rapamycin reduces the amount of nonpathological Q25 by 70% over 3 d, but Q97 accumulation is unaffected. Interestingly, Q47 inclusions form more slowly as a result of constitutive lysosomal degradation, but fasterforming Q97 inclusions escape lysosomal control. Thus, cytoplasmic Q97 inclusions are refractory to clearance by proteasomal and lysosomal systems, leading to a toxicity that dominates over neuroprotective Hsp70. Our findings may explain the rarity of apoptosis but the inevitable cell death associated with polyQ inclusion diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cytoplasmic Inclusions of Htt Exon1 Containing an Expanded Polyglutamine Tract Suppress Execution of Apoptosis in Sympathetic Neurons

King¹,

Goemans²,

Hafiz³

et al. 2008

J. Neurosci.

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“…The cytochrome c release from mitochondria in cytosol was evaluated by an enzyme-linked immunosorbent assay (ELISA) kit (ElabScience, Wuhan, China) [52]. Absorbance value in the samples was measured with the Microplate reader at 450 nm.…”

Section: Measurement Of Cytochrome Cmentioning

confidence: 99%

The metabolites of glutamine prevent hydroxyl radical-induced apoptosis through inhibiting mitochondria and calcium ion involved pathways in fish erythrocytes

Jiang

Liu

et al. 2016

Free Radical Biology and Medicine

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a b s t r a c tThe present study explored the apoptosis pathways in hydroxyl radicals ( • OH)-induced carp erythrocytes. Carp erythrocytes were treated with the caspase inhibitors in physiological carp saline (PCS) or Ca 2 þ -free PCS in the presence of 40 μM FeSO 4 /20 μM H 2 O 2 . The results showed that the generation of reactive oxygen species (ROS), the release of cytochrome c and DNA fragmentation were caspase-dependent, and Ca 2 þ was involved in calpain activation and phosphatidylserine (PS) exposure in • OH-induced carp erythrocytes. Moreover, the results suggested that caspases were involved in PS exposure, and Ca 2 þ was involved in DNA fragmentation in • OH-induced fish erythrocytes. These results demonstrated that there might be two apoptosis pathways in fish erythrocytes, one is the caspase and cytochrome c-dependent apoptosis that is similar to that in mammal nucleated cells, the other is the Ca 2 þ -involved apoptosis that was similar to that in mammal non-nucleated erythrocytes. So, fish erythrocytes may be used as a model for studying oxidative stress and apoptosis in mammal cells. Furthermore, the present study investigated the effects of glutamine (Gln)'s metabolites [alanine (Ala), citrulline (Cit), proline (Pro) and their combination (Ala 10 Pro 4 Cit 1 )] on the pathways of apoptosis in fish erythrocytes. The results displayed that Ala, Cit, Pro and Ala 10 Pro 4 Cit 1 effectively suppressed ROS generation, cytochrome c release, activation of caspase-3, caspase-8 and caspase-9 at the physiological concentrations, prevented Ca 2 þ influx, calpain activation, PS exposure, DNA fragmentation and the degradation of the cytoskeleton and oxidation of membrane and hemoglobin (Hb) and increased activity of anti-hydroxyl radical (AHR) in • OH-induced carp erythrocytes. Ala 10 Pro 4 Cit 1 produced a synergistic effect of inhibited oxidative stress and apoptosis in fish erythrocytes. These results demonstrated that Ala, Cit, Pro and their combination can protect mammal erythrocytes and nucleated cells against oxidative stress and apoptosis. The studies supported the use of Gln, Ala, Cit and Pro as oxidative stress and apoptosis inhibitors in mammal cells and the hypothesis that the inhibited effects of Gln on oxidative stress and apoptosis are at least partly dependent on that of its metabolites in mammalian.

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“…Reports are available showing that melatonin is a remarkably potent neuroprotective agent in mutanthuntingtin (mutant-htt) ST14A cells, a cellular model of HD [136][137][138]. Furthermore, melatonin prevents cell death of primary cortical neurons that have been challenged with proapoptotic inducer [139]. Melatonin treatment counteracted the mitochondrial cell death pathways through the inhibition of the release of Smac (small mitochondria-derived activator of caspases) and the activation of caspase-9 in apoptotic mutanthtt ST14A striatal cells [30,140].…”

Section: Melatonin In Huntington's Disease (Hd)mentioning

confidence: 99%

Promising Role of Melatonin as Neuroprotectant in Neurodegenerative Pathology

et al. 2014

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Melatonin treatment showed a potent neuroprotective action in experimental models and in clinical studies. However, the entire disease prevention is not observed with melatonin treatment. Therefore, findings have suggested its future use in combination therapies for neurological diseases. Several studies have showed its free radical scavenging, antioxidant property, antiapoptotic activity, and its action towards enhanced mitochondrial function. It has direct and indirect effects on mitochondrial functions. Neurodegenerative disease pathology includes the impaired mitochondrial functions and apoptotic death of neurons due to energy crisis which could be prevented with antiapoptotic activity of melatonin. However, for the therapeutic use of melatonin, researchers also need to pay attention towards the various intermediary events taking place in apoptotic death of neurons during disease pathology. Age-related neurological diseases include the decreased level of melatonin in neuronal death. Therefore, it is worthwhile to discuss about the different functions of melatonin in aspect of its antioxidative property, its role in the enhancement of mitochondrial function, and its antiapoptotic attributes. This review summarizes the reports to date showing the potent role of melatonin in experimental models and clinical trials and discussing the employment of melatonin as future potent neuroprotective agent.

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Inhibitors of CytochromecRelease with Therapeutic Potential for Huntington's Disease

Cited by 102 publications

References 50 publications

Cytoplasmic Inclusions of Htt Exon1 Containing an Expanded Polyglutamine Tract Suppress Execution of Apoptosis in Sympathetic Neurons

Cytoplasmic Inclusions of Htt Exon1 Containing an Expanded Polyglutamine Tract Suppress Execution of Apoptosis in Sympathetic Neurons

The metabolites of glutamine prevent hydroxyl radical-induced apoptosis through inhibiting mitochondria and calcium ion involved pathways in fish erythrocytes

Promising Role of Melatonin as Neuroprotectant in Neurodegenerative Pathology

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