Oxidative stress activates the c-Abl/p73 proapoptotic pathway in Niemann-Pick type C neurons

Klein, Andrés D.; Maldonado, Carola; Vargas, Lina; González, Marcela; Robledo, Fermín; Arce, Karen Perez de; Muñoz, Francisco J.; Hetz, Claudio; Álvarez, Alejandra; Zanlungo, Silvana

doi:10.1016/j.nbd.2010.09.008

Cited by 56 publications

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“…For instance, we have shown that treatment with the antioxidant N -Acetyl Cysteine (NAC) prevented c-Abl/p73 activation and apoptosis in in vitro NPC-like neurons [24]. However, oral supplementation of NAC only partially improved liver function and moderately reduced neurologic symptoms of Npc1 −/− mice [15,23].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, an increase in cholesterol oxidation products, such as 7-ketocholesterol (7-KC) and 3β,5α,6β-cholestanetriol (3β,5α,6β-triol) has been detected in NPC1 patients as well as in Npc1 −/− mice, whose levels seem to correlate with the severity and progression of the disease [21,22,23]. Interestingly, previous work from our group demonstrates that oxidative stress is the main upstream stimulus activating apoptosis in NPC neurons through the c-Abl/p73 proapoptotic pathway [24]. For instance, we have shown that treatment with the antioxidant N -Acetyl Cysteine (NAC) prevented c-Abl/p73 activation and apoptosis in in vitro NPC-like neurons [24].…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, previous work from our group demonstrates that oxidative stress is the main upstream stimulus activating apoptosis in NPC neurons through the c-Abl/p73 proapoptotic pathway [24]. For instance, we have shown that treatment with the antioxidant N -Acetyl Cysteine (NAC) prevented c-Abl/p73 activation and apoptosis in in vitro NPC-like neurons [24]. However, oral supplementation of NAC only partially improved liver function and moderately reduced neurologic symptoms of Npc1 −/− mice [15,23].…”

Section: Introductionmentioning

confidence: 99%

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Vitamin E Dietary Supplementation Improves Neurological Symptoms and Decreases c-Abl/p73 Activation in Niemann-Pick C Mice

et al. 2014

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Niemann-Pick C (NPC) disease is a fatal neurodegenerative disorder characterized by the accumulation of free cholesterol in lysosomes. We have previously reported that oxidative stress is the main upstream stimulus activating the proapoptotic c-Abl/p73 pathway in NPC neurons. We have also observed accumulation of vitamin E in NPC lysosomes, which could lead to a potential decrease of its bioavailability. Our aim was to determine if dietary vitamin E supplementation could improve NPC disease in mice. NPC mice received an alpha-tocopherol (α-TOH) supplemented diet and neurological symptoms, survival, Purkinje cell loss, α-TOH and nitrotyrosine levels, astrogliosis, and the c-Abl/p73 pathway functions were evaluated. In addition, the effect of α-TOH on the c-Abl/p73 pathway was evaluated in an in vitro NPC neuron model. The α-TOH rich diet delayed loss of weight, improved coordination and locomotor function and increased the survival of NPC mice. We found increased Purkinje neurons and α-TOH levels and reduced astrogliosis, nitrotyrosine and phosphorylated p73 in cerebellum. A decrease of c-Abl/p73 activation was also observed in the in vitro NPC neurons treated with α-TOH. In conclusion, our results show that vitamin E can delay neurodegeneration in NPC mice and suggest that its supplementation in the diet could be useful for the treatment of NPC patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Vitamin E Dietary Supplementation Improves Neurological Symptoms and Decreases c-Abl/p73 Activation in Niemann-Pick C Mice

et al. 2014

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“…Concentrations of ROS and lipid peroxidation were higher in fibroblasts from NPC patients than in fibroblasts from normal subjects (63). Oxidative stress is the main upstream stimulus activating apoptosis in NPC neurons (64,65). Studies from NPC patients showed significant reduction in both antioxidant capacity (expressed as Trolox equivalents) and reduced coenzyme Q10 in serum compared with controls (20).…”

Section: Corroboration Of Deps In Our Data Set With Previousmentioning

confidence: 99%

Quantitative Proteomics of Human Fibroblasts with I1061T Mutation in Niemann–Pick C1 (NPC1) Protein Provides Insights into the Disease Pathogenesis*

Rauniyar¹,

Subramanian

Lavallée‐Adam³

et al. 2015

Molecular & Cellular Proteomics

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Niemann-Pick type C (NPC) disease is a fatal neurodegenerative disorder characterized by the accumulation of unesterified cholesterol in the late endosomal/lysosomal compartments. Mutations in the NPC1 protein are implicated in 95% of patients with NPC disease. The most prevalent mutation is the missense mutation I1061T that occurs in ϳ15-20% of the disease alleles. In our study, an isobaric labeling-based quantitative analysis of proteome of NPC1I1061T primary fibroblasts when compared with wild-type cells identified 281 differentially expressed proteins based on stringent data analysis criteria. Gene ontology enrichment analysis revealed that these proteins play important roles in diverse cellular processes such as protein maturation, energy metabolism, metabolism of reactive oxygen species, antioxidant activity, steroid metabolism, lipid localization, and apoptosis. The relative expression level of a subset of differentially expressed proteins (TOR4A, DHCR24, CLGN, SOD2, CHORDC1, HSPB7, and GAA) was independently and successfully substantiated by Western blotting. We observed that treating NPC1I1061T cells with four classes of seven different compounds that are potential NPC drugs increased the expression level of SOD2 and DHCR24. We have also shown an abnormal accumulation of glycogen in NPC1 I1061T fibroblasts possibly triggered by defective processing of lysosomal alpha-glucosidase. Our study provides a starting point for future more focused investigations to better understand the mechanisms by which the reported dysregulated proteins triggers the pathological cascade in NPC, and furthermore, their effect upon therapeutic interventions.

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“…Кроме того, оказалось, что белки, вовлеченные в ОКМС, способны регулировать деградацию белков нейронального апоптоза по типу связи «degradation downregulation». Например, белок JNK1, который активируется под влиянием механи-ческого стресса (Zhou et al, 2007), способен увеличивать стабильность белка P73 (Ozaki et al, 2010), являющегося в нейронах проапоптотическим белком (Klein et al, 2011). Из выявленных взаимодействий видно, что регуляция белков и генов нейронального апоптоза со стороны ответа клетки на механический стресс может быть направлена на активацию процесса апоптоза посредством положитель-ной регуляции экспрессии генов и стабильности белков, вовлеченных в нейрональный апоптоз, что согласуется с известными данными (Calandrella et al, 2007;Slemmer et al, 2008;Uchida et al, 2008).…”

Section: результаты и обсуждениеunclassified

Molecular-genetic mechanisms of the interaction between processes of cell response to mechanical stress and neuronal apoptosis in primary open-angle glaucoma

Saik¹,

Konovalova²,

Деменков³

et al. 2016

Vestn. VOGiS

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Glaucoma is a chronic and progressive disease, which affects more than 60 million people worldwide. Pri mary open-angle glaucoma (POAG) is one of the most common forms of glaucoma. For example, about 2.71 million people in the USA had primary open-angle glaucoma in 2011. Currently POAG is a major cause of irreversible vision loss. In patients with treated open-angle glaucoma the risk of blindness reached to be about 27 %. It is known that the death of optic nerve cells can be triggered by mechanical stress caused by increased intraocular pressure, which induces neuronal apoptosis and is observed in patients with POAG. Currently, there is a large number of scientific publications describing proteins and genes involved in the pathogenesis of POAG, including neuronal apoptosis and the cell response to mechanical stress. However, the molecu lar-genetic mechanisms underlying the pathophysiology of POAG are still poorly understood. Reconstruction of associative networks describing the functional interactions between these genes/proteins, including biochemical reactions, regulatory interactions, transport, etc., requires the use of methods of automated knowledge Глаукома -хроническое, прогрессирующее заболевание, кото-рым страдают более 60 млн человек в мире. Первичная открыто-угольная глаукома (ПОУГ) занимает одно из первых мест по рас-пространенности среди различных форм глаукомы. Например, в 2011 г. эта форма заболевания наблюдалась более чем у 2.7 млн человек в США. В настоящее время ПОУГ является основной при-чиной необратимой потери зрения. У больных с открытоуголь-ной глаукомой риск слепоты достигает 27 %, даже несмотря на проводимое лечение. Известно, что гибель клеток зрительного нерва может быть спровоцирована механическим стрессом, вы-званным повышенным внутриглазным давлением, наблюда ющим-ся при ПОУГ, индуцирующим нейрональный апоптоз. В настоящее время существует огромное количество научных публикаций, описывающих белки и гены, которые участвуют в патогенезе ПОУГ, в том числе в нейрональном апоптозе и клеточном ответе на механический стресс. Тем не менее молекулярно-генетические механизмы, лежащие в основе патофизиологии ПОУГ, до сих пор плохо изучены. Реконструкция ассоциативных генных сетей, опи-сывающих функциональные взаимодействия между этими генами/ белками, включая биохимические реакции, регуляторные взаимо-действия, события транспорта и т. д., требует использования методов автоматизированного извлечения знаний из текстов научных публикаций. В работе проанализированы ассоциативные сети, описывающие молекулярно-генетические взаимодействия между белками и генами, вовлеченными в ответ клетки на меха-нический стресс (ОКМС), нейрональный апоптоз и патогенез ПОУГ. Показано, что гены, ассоциированные с ПОУГ, статистически значимо чаще, чем ожидалось по случайным причинам, представ-лены среди генов, участвующих во взаимодействии между ОКМС и нейрональным апоптозом, что может быть важным фактором, влияющим на гибель ганглиозных ретинальных клеток при ПОУГ. Ключевые

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Oxidative stress activates the c-Abl/p73 proapoptotic pathway in Niemann-Pick type C neurons

Cited by 56 publications

References 44 publications

Vitamin E Dietary Supplementation Improves Neurological Symptoms and Decreases c-Abl/p73 Activation in Niemann-Pick C Mice

Vitamin E Dietary Supplementation Improves Neurological Symptoms and Decreases c-Abl/p73 Activation in Niemann-Pick C Mice

Quantitative Proteomics of Human Fibroblasts with I1061T Mutation in Niemann–Pick C1 (NPC1) Protein Provides Insights into the Disease Pathogenesis*

Molecular-genetic mechanisms of the interaction between processes of cell response to mechanical stress and neuronal apoptosis in primary open-angle glaucoma

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