Inhibition of Calcineurin by FK506 Protects against Polyglutamine-Huntingtin Toxicity through an Increase of Huntingtin Phosphorylation at S421

Pardo, Raúl; Colin, Emilie; Régulier, Etienne; Aebischer, Patrick; Déglon, Nicole; Humbert, Sandrine

doi:10.1523/jneurosci.3706-05.2006

Cited by 119 publications

(135 citation statements)

References 76 publications

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“…Changes in phosphorylation of htt occur within minutes after NMDA stimulation (data not shown), and this is far more likely a direct consequence of phosphatase activation. In fact, htt has recently been identified as a substrate for protein phosphatase 2B (PP2B/ calcineurin) (Luo et al, 2005;Pardo et al, 2006), and dephosphorylation of P-Akt-S473 (Sutton and Chandler, 2002), P-GSK3␤-S9 (Szatmari et al, 2005), and P-CREB-S133 (Sala et al, 2000;Kopnisky et al, 2003) during NMDA-induced excitotoxicity is the result of PP1 activity.…”

Section: Discussionmentioning

confidence: 99%

NMDA Receptor Function and NMDA Receptor-Dependent Phosphorylation of Huntingtin Is Altered by the Endocytic Protein HIP1

Metzler¹,

Gan²,

Wong³

et al. 2007

J. Neurosci.

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Huntingtin-interacting protein 1 (HIP1) is an endocytic adaptor protein that plays a role in clathrin-Ϫ/Ϫ neurons, respectively. In summary, we have shown that HIP1 influences important NMDAR functions and that both HIP1 and htt participate in NMDA-induced cell death. These findings may provide novel insights into the cellular mechanisms underlying enhanced NMDA-induced excitotoxicity in Huntington's disease.

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Section: Discussionmentioning

confidence: 99%

NMDA Receptor Function and NMDA Receptor-Dependent Phosphorylation of Huntingtin Is Altered by the Endocytic Protein HIP1

Metzler¹,

Gan²,

Wong³

et al. 2007

J. Neurosci.

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“…Htt is itself a phosphoprotein with a toxicity when mutated that is regulated by phosphorylation (Humbert et al, 2002;Rangone et al, 2004;Luo et al, 2005;Warby et al, 2005;Pardo et al, 2006;Schilling et al, 2006). Cdk5 phosphorylates htt at S434 and regulates its proteolysis (Luo et al, 2005).…”

Section: Cdk5 Phosphorylates Huntingtin At Serines 1181 and 1201 In Vmentioning

confidence: 99%

“…In disease, polyQ expansion in htt leads to a reduction of BDNF transcription and transport, thereby reducing neurotrophic support (Zuccato et al, 2001;Gauthier et al, 2004). Arguments for a key role of the protein context in pathogenesis also come from the observations that cleavage and posttranslational modifications regulate the toxicity of polyQ-htt (Humbert et al, 2002; (Humbert et al, 2002;Warby et al, 2005;Pardo et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation of Huntingtin by Cyclin-Dependent Kinase 5 Is Induced by DNA Damage and Regulates Wild-Type and Mutant Huntingtin Toxicity in Neurons

Anne¹,

Saudou²,

Humbert³

2007

J. Neurosci.

114

120

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Huntingtin is an antiapoptotic protein that becomes toxic when its polyglutamine stretch is expanded, resulting in Huntington's disease (HD). Protein context and posttranslational modifications regulate huntingtin toxicity. Identifying signaling pathways that act on huntingtin is, therefore, key to understanding huntingtin function in normal and pathological conditions. We show here that huntingtin is phosphorylated by the cyclin-dependent kinase 5 (Cdk5) at serines 1181 and 1201. Phosphorylation can be induced by DNA damage in vitro and in vivo. The state of huntingtin phosphorylation is a crucial regulator of neuronal cell death. Absence of phosphorylation of huntingtin at serines 1181 and 1201 confers toxic properties to wild-type huntingtin in a p53-dependent manner in striatal neurons and accelerates neuronal death induced by DNA damage. In contrast, phosphorylation at serines 1181 and 1201 protects against polyQinduced toxicity. Finally, we show in late stages of HD a sustained DNA damage that is associated with a decrease in Cdk5/p35 levels. We propose that wild-type huntingtin is a component of the DNA damage response signal in neurons and that the Cdk5/DNA damage pathway is dysregulated in HD.

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“…Htt can be phosphorylated at serine 421 by protein kinase Akt (also known as PKB) and serum-and glucocorticoid-induced kinase (SGK). In vitro and in vivo studies indicate that this phosphorylation can protect against the toxicity of polyQ-expanded Htt [5,[31][32][33][34] . Another crucial kinase involved in the pathway leading to HD pathogenesis is cyclin-dependent kinase 5 (CDK5), a serine-threonine kinase.…”

Section: Htt Phosphorylation and Hd Phosphorylation Of Htt Atmentioning

confidence: 99%

亨廷顿蛋白的翻译后修饰在亨廷顿病发病机制中的作用

2010

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Inhibition of Calcineurin by FK506 Protects against Polyglutamine-Huntingtin Toxicity through an Increase of Huntingtin Phosphorylation at S421

Cited by 119 publications

References 76 publications

NMDA Receptor Function and NMDA Receptor-Dependent Phosphorylation of Huntingtin Is Altered by the Endocytic Protein HIP1

NMDA Receptor Function and NMDA Receptor-Dependent Phosphorylation of Huntingtin Is Altered by the Endocytic Protein HIP1

Phosphorylation of Huntingtin by Cyclin-Dependent Kinase 5 Is Induced by DNA Damage and Regulates Wild-Type and Mutant Huntingtin Toxicity in Neurons

亨廷顿蛋白的翻译后修饰在亨廷顿病发病机制中的作用

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