Inhibition of Autophagy via p53-Mediated Disruption of ULK1 in a SCA7 Polyglutamine Disease Model

Yu, Xin; Muñoz-Alarcón, Andrés; Ajayi, Abiodun; Webling, Kristin; Steinhof, Anne; Langel, Ülo; Ström, Anna-Lena

doi:10.1007/s12031-013-0012-x

Cited by 29 publications

(32 citation statements)

References 51 publications

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“…Using the same stable inducible SCA7 model as in this study, we have previously shown that p53 co-aggregates with mutant ATXN7 and that this reduces the soluble p53 level and transcriptional activity [27]. Consistent with this, we could again in induced FLQ65 cells detect p53 in the insoluble cell fractions containing mutant ATXN7 aggregates; see Fig.…”

Section: Altered P53 Function Contributes To the Metabolic Dysfunctionsupporting

confidence: 87%

“…9), where p53-ATXN7 coaggregation and NOX1-mediated p53 inactivation result in reduced p53 transcriptional activity, metabolic dysregulation and further NOX1 activity, as well as oxidative stress. In fact, we have shown that breaking this proposed cycle, through blockage of p53-ATXN7 co-aggregation [27], increasing p53 levels (Figs. 7-8), as well as inhibiting NOX1 activity or ROS scavenging (Fig.…”

Section: Discussionmentioning

confidence: 87%

“…Cell lysis, filter trap and western blotting were done as previously described [9,27]. In brief, cells were lysed with RIPA buffer (Millipore) and following centrifugation at 21,000 ×g the soluble fractions, i.e.…”

Section: Cell Lysis Filter Trap Assay and Western Blottingmentioning

confidence: 99%

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Altered p53 and NOX1 activity cause bioenergetic defects in a SCA7 polyglutamine disease model

Ajayi

Wahlo-Svedin

et al. 2015

Biochimica et Biophysica Acta (BBA) - Bioenergetics

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Spinocerebellar ataxia type 7 (SCA7) is one of the nine neurodegenerative disorders caused by expanded polyglutamine (polyQ) domains. Common pathogenic mechanisms, including bioenergetics defects, have been suggested for these so called polyQ diseases. However, the exact molecular mechanism(s) behind the metabolic dysfunction is still unclear. In this study we identified a previously unreported mechanism, involving disruption of p53 and NADPH oxidase 1 (NOX1) activity, by which the expanded SCA7 disease protein ATXN7 causes metabolic dysregulation. The NOX1 protein is known to promote glycolytic activity, whereas the transcription factor p53 inhibits this process and instead promotes mitochondrial respiration. In a stable inducible PC12 model of SCA7, p53 and mutant ATXN7 co-aggregated and the transcriptional activity of p53 was reduced, resulting in a 50% decrease of key p53 target proteins, like AIF and TIGAR. In contrast, the expression of NOX1 was increased approximately 2 times in SCA7 cells. Together these alterations resulted in a decreased respiratory capacity, an increased reliance on glycolysis for energy production and a subsequent 20% reduction of ATP in SCA7 cells. Restoring p53 function, or suppressing NOX1 activity, both reversed the metabolic dysfunction and ameliorated mutant ATXN7 toxicity. These results hence not only enhance the understanding of the mechanisms causing metabolic dysfunction in SCA7 disease, but also identify NOX1 as a novel potential therapeutic target in SCA7 and possibly other polyQ diseases.

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Section: Altered P53 Function Contributes To the Metabolic Dysfunctionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 87%

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Altered p53 and NOX1 activity cause bioenergetic defects in a SCA7 polyglutamine disease model

Ajayi

Wahlo-Svedin

et al. 2015

Biochimica et Biophysica Acta (BBA) - Bioenergetics

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“…These pathways are responsible for the clearance and degradation of misfolded and/or superfluous proteins. It stands to reason that these systems are somewhat compromised in SCA patients, and numerous studies have now shown that these systems do in fact exhibit impairment in SCA diseases [61][62][63][64][65]. The dysregulation is believed to play a role in protein aggregation, as the misfolded polyQ proteins are unable to be effectively degraded, which leads to an increased proportion of aggregates.…”

Section: Protein Aggregation: a Hallmark Featurementioning

confidence: 99%

“…The group found that the inhibition of autophagy was through the co-aggregation of p53-FIP200 proteins and ataxin-7 aggregates that resulted in destabilisation of ULK1, due to decreased soluble FIP200. It was further shown that inhibition of P53 is able to restore soluble FIP200 and ULK1, which increases autophagic activity and subsequently reduces mutant ataxin-7 toxicity [62]. Therapeutic strategies targeting the pathogenic autophagic dysregulation would benefit from the understanding of the exact mechanisms by which pathogenesis is caused.…”

Section: Wild-type and Mutant Proteinmentioning

confidence: 99%

Polyglutamine ataxias: From Clinical and Molecular Features to Current Therapeutic Strategies

McIntosh¹,

Htut²,

Fletcher³

et al. 2017

J Genet Syndr Gene Ther

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Spinocerebellar ataxias are a large group of heterogeneous diseases that all involve selective neuronal degeneration and accompanied cerebellar ataxia. These diseases can be further broken down into discrete groups according to their underlying molecular genetic cause. The most common are the polyglutamine ataxias, of which there are six; Spinocerebellar ataxia type 1, 2, 3, 6, 7 and 17. These diseases are characterised by a pathological expanded cytosine-adenine-guanine (CAG) repeat sequence, in the protein coding region of a given gene. Common clinical features include lack of coordination and gait ataxia, speech and swallowing difficulties, as well as impaired hand and motor functions. The polyglutamine spinocerebellar ataxias are typically late onset diseases that are progressive in nature and often lead to premature death, for which there is currently no known cure or effective treatment strategy. Although caused by the same molecular mechanism, the causative gene and associated protein differ for each disease. The exact mechanism by which disease pathogenesis is caused remains elusive. However, the variable (CAG) n repeats are codons that may be translated to an expanded glutamine tract, leading to conformational changes in the protein, giving it a toxic gain of function. Several pathogenic pathways have been implicated in polyglutamine spinocerebellar ataxia diseases, such as the hallmark feature of neuronal nuclear inclusions, protein misfolding and aggregation, as well as transcriptional dysregulation. These pathways are attractive avenues for potential therapeutic interventions, as the potential to treat more than one disease exists. Research is ongoing, and several promising therapies are currently underway in an attempt to provide relief for this devastating class of diseases.. However, mutations can arise de novo, through errors in DNA replication such that two genetically healthy parents can give rise to an affected child.There are currently six characterised polyQ SCAs (1, 2, 3, 6, 7 and 17) (Table 1), and together with three other diseases, namely Huntington's disease, spinal and bulbar muscular atrophy and dentatorubropallidoluysian atrophy (DRPLA), form a larger category of polyQ diseases [7][8][9][10]. Th ere is little relief for individuals suffering from polyQ SCA disorders, with symptomatic treatments the only available option. Long term pharmacological treatment, although admirable, tends to fall short in an effective management strategy, as unwanted complications and low drug efficacy still exist. In addition, none of these diseases have any treatments that slow the progression of the disease; leaving affected individuals with the daunting reality that time may be a severe limiting factor. Several experimental approaches are currently being assessed to overcome these difficulties. This review will focus on the clinical and molecular features of polyQ SCA diseases (which will be referred to as SCA diseases), as well as highlight several promising and emerging therapeutic strategies...

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Ulk1/FUNDC1 Prevents Nerve Cells from Hypoxia-Induced Apoptosis by Promoting Cell Autophagy

Wang

Dong

et al. 2018

Neurochem Res

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Cell autophagy and cell apoptosis are both observed in the process of hypoxia-induced ischemic cerebral infarction (ICI). Unc-51 like autophagy activating kinase 1 (Ulk1) and FUN14 Domain-containing Protein 1 (FUNDC1) are both involved in the regulation of cell autophagy. This study aimed to investigate the regulatory effects of Ulk1 and FUNDC1 on hypoxia-induced nerve cell autophagy and apoptosis. Cell viability was measured using cell counting kit-8 (CCK-8) assay. Cell apoptosis was detected using Annexin V-PE/7-ADD staining assay. qRT-PCR was used to quantify the mRNA levels of Ulk1 and FUNDC1 in PC-12 cells. Cell transfection was performed to up-regulate the expression of Ulk1. 3-Methyladenine (3-MA) was used as autophagy inhibitor and rapamycin was used as autophagy activator in our experiments. SP600125 was used as c-Jun N-terminal kinase (JNK) inhibitor. Western blotting was performed to analyze the expression levels of key factors that are related to cell autophagy, apoptosis and JNK pathway. We found that hypoxia simultaneously induced apoptosis and autophagy of PC-12 cells. The activation of Ulk1 and FUNDC1 were also found in PC-12 cells after hypoxia induction. Overexpression of Ulk1 promoted the activation of FUNDC1 and prevented PC-12 cells from hypoxia-induced apoptosis. Suppression of Ulk1 had opposite effects. Furthermore, we also found that JNK pathway participated in the effects of Ulk1 overexpression on PC-12 cell apoptosis reduction. To conclude, Ulk1/FUNDC1 played critical regulatory roles in hypoxia-induced nerve cell autophagy and apoptosis. Overexpression of Ulk1 prevented nerve cells from hypoxia-induced apoptosis by promoting cell autophagy.

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Inhibition of Autophagy via p53-Mediated Disruption of ULK1 in a SCA7 Polyglutamine Disease Model

Cited by 29 publications

References 51 publications

Altered p53 and NOX1 activity cause bioenergetic defects in a SCA7 polyglutamine disease model

Altered p53 and NOX1 activity cause bioenergetic defects in a SCA7 polyglutamine disease model

Polyglutamine ataxias: From Clinical and Molecular Features to Current Therapeutic Strategies

Ulk1/FUNDC1 Prevents Nerve Cells from Hypoxia-Induced Apoptosis by Promoting Cell Autophagy

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