PH domain leucine-rich repeat protein phosphatase 1 contributes to maintain the activation of the PI3K/Akt pro-survival pathway in Huntington's disease striatum

Saavedra, Ana; García‐Martínez, Juan Manuel; Xifró, Xavier; Giralt, Albert; Torres-Peraza, Jesús F.; Canals, Josep M.; Dı́az-Hernández, Miguel; Lucas, José J.; Alberch, Jordi; Pérez‐Navarro, Esther

doi:10.1038/cdd.2009.127

Cited by 50 publications

(73 citation statements)

References 45 publications

(85 reference statements)

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“…In addition, we examined the protein levels of several neuronal markers whose expression is strongly decreased in striatal cells expressing mutant HTT (20)(21)(22)(23)(24)(25) (Figure 4). Treatment with LNA-CTG resulted in a significant recovery of protein levels of the PH domain and leucine-rich repeat protein phosphatase 1 (PHLPP1), dopamine-and cyclic AMP-regulated phosphoprotein of 32 kDa (DARPP-32), striatal-enriched protein tyrosine phosphatase 46 (STEP46), and postsynaptic density protein 95 (PSD95).…”

Section: Resultsmentioning

confidence: 99%

Targeting CAG repeat RNAs reduces Huntington’s disease phenotype independently of huntingtin levels

Rué¹,

Báñez-Coronel²,

Creus-Muncunill³

et al. 2016

Journal of Clinical Investigation

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Section: Resultsmentioning

confidence: 99%

Targeting CAG repeat RNAs reduces Huntington’s disease phenotype independently of huntingtin levels

Rué¹,

Báñez-Coronel²,

Creus-Muncunill³

et al. 2016

Journal of Clinical Investigation

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“…PI3K and CREB are established to function as pro-survival signals (36)(37)(38)(39)(40). In the present study, PI3K activity and CREB phosphorylation were reduced in MC3T3-E1 cells after H 2 O 2 treatment, whereas allicin treatment prevented the reduction of PI3K activity and CREB phosphorylation.…”

Section: A B C Dmentioning

confidence: 46%

Allicin inhibits oxidative stress-induced mitochondrial dysfunction and apoptosis by promoting PI3K/AKT and CREB/ERK signaling in osteoblast cells

Ding

Zhao

Jiang

2016

Experimental and Therapeutic Medicine

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Abstract.Osteoporosis is a disease of the skeleton that is characterized by the loss of bone mass and degeneration of bone microstructure, resulting in an increased risk of fracture. Oxidative stress, which is known to promote oxidative damage to mitochondrial function and also cell apoptosis, has been recently indicated to be implicated in osteoporosis. However, there are few agents that counteract oxidative stress in osteoporosis. In the present study, the protective effects of allicin against the oxidative stress-induced mitochondrial dysfunction and apoptosis were investigated in murine osteoblast-like MC3T3-E1 cells. The results demonstrated that allicin counteracted the reduction of cell viability and induction of apoptosis caused by hydrogen peroxide (H 2 O 2 ) exposure. The inhibition of apoptosis by allicin was confirmed by the inhibition of H 2 O 2 -induced cytochrome c release and caspase-3 activation. Moreover, the inhibition of apoptosis by allicin was identified to be associated with the counteraction of H 2 O 2 -induced mitochondrial dysfunction. In addition, allicin was demonstrated to be able to significantly ameliorate the repressed phosphoinositide 3-kinase (PI3K)/AKT and cyclic adenosine monophosphate response element-binding protein (CREB)/extracellular-signal-regulated kinase (ERK) signaling pathways by H 2 O 2 , which may also be associated with the anti-oxidative stress effects of allicin. In conclusion, allicin protects osteoblasts from H 2 O 2 -induced oxidative stress and apoptosis in MC3T3-E1 cells by improving mitochondrial function and the activation of PI3K/AKT and CREB/ERK signaling. The present study implies a promising role of allicin in oxidative stress-associated osteoporosis.

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“…In fact, several kinases and phosphatases have been reported to be altered in HD patients and animal models. Some of these kinases altered in HD are closely related to synaptic plasticity, cell survival and transcriptional regulation such as cAMP-dependent protein kinase (PKA) [59], the kinase Akt [60,61], the mitogen-activated protein kinases (MAPKs) [62][63][64] and kinases downstream MAPK pathway [65][66][67]. Furthermore, also several phosphatases are altered in HD mouse models.…”

Section: Breaking Signaling Pathwaysmentioning

confidence: 99%

“…Furthermore, also several phosphatases are altered in HD mouse models. Some examples are the phosphatase calcineurin [68,69], the PH domain and leucine-rich repeat protein phosphatases (PHLPP) [61] and the striatal-enriched protein tyrosine phosphatase (STEP) [61]. Therefore, therapies with potential to modulate cell signaling pathways could provide protection against neurodegeneration [70,71].…”

Section: Breaking Signaling Pathwaysmentioning

confidence: 99%

See 1 more Smart Citation

Pathogenesis of Huntington’s Disease: How to Fight Excitotoxicity and Transcriptional Dysregulation

Anglada-Huguet¹,

Vidal-Sancho²,

Cabezas-Llobet³

et al. 2017

Huntington's Disease - Molecular Pathogenesis and Current Models

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Huntington's disease (HD) is a neurodegenerative disorder caused by an expanded CAG repeat in the exon-1 of the huntingtin (htt) gene. The presence of mutant htt (mhtt) results in multiple physiopathological changes, including protein aggregation, transcriptional deregulation, decreased trophic support, alteration in signaling pathways and excitotoxicity. Indeed, the presence of mhtt induces changes in the activities/levels of different kinases, phosphatases and transcription factors that can impact on cell survival. Many studies have provided evidence that transcription may be a major target of mhtt, as gene dysregulation occurs before the onset of symptoms. The greatest number of downregulated genes in HD has led to test the ability of a large number of compounds to restore gene transcription in mouse models of HD. On the other hand, mhtt engenders multiple cellular dysfunctions including an increase of pathological glutamate-mediated excitotoxicity. For that reason, targeting the excess of glutamate has been the goal for many promising drugs leading to clinical trials. Although advances in developing effective therapies are evident, currently, there is no known cure for HD and existing symptomatic treatments are limited.

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PH domain leucine-rich repeat protein phosphatase 1 contributes to maintain the activation of the PI3K/Akt pro-survival pathway in Huntington's disease striatum

Cited by 50 publications

References 45 publications

Targeting CAG repeat RNAs reduces Huntington’s disease phenotype independently of huntingtin levels

Targeting CAG repeat RNAs reduces Huntington’s disease phenotype independently of huntingtin levels

Allicin inhibits oxidative stress-induced mitochondrial dysfunction and apoptosis by promoting PI3K/AKT and CREB/ERK signaling in osteoblast cells

Pathogenesis of Huntington’s Disease: How to Fight Excitotoxicity and Transcriptional Dysregulation

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