Polyglutamine-expanded ataxin-7 upregulates Bax expression by activating p53 in cerebellar and inferior olivary neurons

Wang, Hung Li; Chou, An Hsun; Lin, An Chi; Chen, Si Ying; Weng, Yi Hshin; Yeh, Tu Hsueh

doi:10.1016/j.expneurol.2010.05.011

Cited by 28 publications

(25 citation statements)

References 26 publications

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“…Previous studies by us and others showed that a high level of PDGF-b promotermediated neuronal transgene expression was observed in the cerebral cortex, striatum, and SN. [22][23][24] Furthermore, hybrid CMV enhancer/PDGF-b promoter mediated a high level of transgene expression in SNpc dopaminergic neurons. 25 Therefore, the expression of (G2019S) or wild-type LRRK2HA in the transgenic mouse was under transcriptional control of CMV enhancer/PDGF-b promoter.…”

Section: Resultsmentioning

confidence: 99%

“…PDGF-b promoter mediated a high level of neuronal transgene expression in the brain. [22][23][24] Furthermore, hybrid CMV enhancer/PDGF-b promoter drives a highly efficient transgene expression in SNpc dopaminergic neurons. 25 Thus, we prepared (G2019S) LRRK2-induced PD mouse model expressing transgene CMV enhancer/PDGF-b promoter-(G2019S) LRRK2.…”

Section: Discussionmentioning

confidence: 99%

“…Oligonucleotide-directed mutagenesis was performed to prepare cDNA encoding human (G2019S) LRRK2, and DNA mutation of LRRK2 was confirmed by DNA sequencing. According to our previous studies, 23,24 transgene construct was prepared by inserting cDNA of HA-tagged wild-type or mutant (G2019S) LRRK2 into CMV enhancer/platelet-derived growth factor (PDGF)-bchain expression vector. An B11-kb transgene fragment contained CMV enhancer, PDGF-bchain promoter, cDNA of wild-type or mutant (G2019S) LRRK2 and a 3' SV40pA sequence.…”

Section: Methodsmentioning

confidence: 99%

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(G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD

Yh²,

et al. 2012

Cell Death Differ

155

151

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(G2019S) mutation of leucine-rich repeat kinase 2 (LRRK2) is the most common genetic cause of both familial and sporadic Parkinson's disease (PD) cases. Twelve-to sixteen-month-old (G2019S) LRRK2 transgenic mice prepared by us displayed progressive degeneration of substantia nigra pars compacta (SNpc) dopaminergic neurons and parkinsonism phenotypes of motor dysfunction. LRRK2 is a member of mixed lineage kinase subfamily of mitogen-activated protein kinase kinase kinases (MAPKKKs). We hypothesized that (G2019S) mutation augmented LRRK2 kinase activity, leading to overphosphorylation of downstream MAPK kinase (MKK) and resulting in activation of neuronal death signal pathway. Consistent with our hypothesis, (G2019S) LRRK2 expressed in HEK 293 cells exhibited an augmented kinase activity of phosphorylating MAPK kinase 4 (MKK4) at Ser 257 , and protein expression of active phospho-MKK4 Ser257 was upregulated in the SN of (G2019S) LRRK2 transgenic mice. Protein level of active phospho-JNK Thr183/Tyr185 and phospho-c-Jun Ser63 , downstream targets of phospho-MKK4 Ser257 , was increased in the SN of (G2019S) LRRK2 mice. Upregulated mRNA expression of pro-apoptotic Bim and FasL, target genes of phospho-c-Jun Ser63 , and formation of active caspase-9, caspase-8 and caspase-3 were also observed in the SN of (G2019S) LRRK2 transgenic mice. Our results suggest that mutant (G2019S) LRRK2 activates MKK4-JNK-c-Jun pathway in the SN and causes the resulting degeneration of SNpc dopaminergic neurons in PD transgenic mice.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

(G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD

Yh²,

et al. 2012

Cell Death Differ

155

151

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“…Several studies have implicated altered p53-mediated transcriptional activity and apoptosis in polyQ diseases (Bae et al, 2005;Chou et al, 2011;Grison et al, 2011;Illuzzi et al, 2011;Shahbazian et al, 2001;Steffan et al, 2000;Tsoi et al, 2012;Wang et al, 2010). However, to our knowledge no studies investigating the effects of mutant polyQ proteins on p53-mediated regulation of autophagy have so far been published.…”

Section: Discussionmentioning

confidence: 99%

“…As p53 is a known autophagy regulator and altered p53 activity has been implicated in polyQ pathology, we examined the level and sub-cellular localization of p53 in FLQ10 and FLQ65 cells (Bae et al, 2005;Chou et al, 2011;Grison et al, 2011;Illuzzi et al, 2011;Shahbazian et al, 2001;Steffan et al, 2000;Tsoi et al, 2012;Wang et al, 2010). In FLQ10 cells p53…”

Section: The Sub-cellular Localization Of P53 Is Altered In Mutant Atmentioning

confidence: 99%

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

Muñoz-Alarcón

Ajayi

et al. 2013

J Mol Neurosci

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However, recently evidence implicating autophagic dysfunction in these disorders has also been reported. In this study we show that the SCA7 polyglutamine protein ataxin-7 (ATXN7) reduces the autophagic activity via a previously unreported mechanism involving p53-mediated disruption of two key proteins involved in autophagy initiation. We show that in mutant ATXN7 cells, an increased p53-FIP200 interaction and co-aggregation of p53-FIP200 into ATXN7 aggregates result in decreased soluble FIP200 levels and subsequent destabilization of ULK1. Together, this leads to a decreased capacity for autophagy induction via the ULK1-FIP200-Atg13-Atg101 complex. We also show that treatment with a p53 inhibitor, or a blocker of ATXN7 aggregation, can restore the soluble levels of FIP200 and ULK1, as well as increase the autophagic activity and reduce ATXN7 toxicity. Understanding the mechanism behind polyQ-mediated inhibition of autophagy is of importance if therapeutic approaches based on autophagy stimulation should be developed for these disorders.

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Coenzyme Q10 and spinocerebellar ataxias

Figueroa

Pulst

et al. 2014

Movement Disorders

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The aim of this study was to investigate the association between drug exposure and disease severity in SCA types 1, 2, 3 and 6. The Clinical Research Consortium for Spinocerebellar Ataxias (CRC-SCA) enrolled 319 participants with SCA1, 2, 3, and 6 from 12 medical centers in the United States and repeatedly measured clinical severity by the Scale for Assessment and Rating of Ataxia (SARA), the Unified Huntington's Disease Rating Scale part IV (UHDRS-IV), and the 9-item Patient Health Questionnaire during July 2009 to May 2012. We employed generalized estimating equations in regression models to study the longitudinal effects of coenzyme Q10 (CoQ10), statin, and vitamin E on clinical severity of ataxia after adjusting for age, sex, and pathological CAG repeat number. Cross-sectionally, exposure to CoQ10 was associated with lower SARA and higher UHDRS-IV scores in SCA1 and 3. No association was found between statins, vitamin E, and clinical outcome. Longitudinally, CoQ10, statins, and vitamin E did not change the rates of clinical deterioration indexed by SARA and UHDRS-IV scores within 2 years. CoQ10 is associated with better clinical outcome in SCA1 and 3. These drug exposures did not appear to influence clinical progression within 2 years. Further studies are warranted to confirm the association.

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Polyglutamine-expanded ataxin-7 upregulates Bax expression by activating p53 in cerebellar and inferior olivary neurons

Cited by 28 publications

References 26 publications

(G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD

(G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD

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

Coenzyme Q10 and spinocerebellar ataxias

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