Increased 90-kDa ribosomal S6 kinase (Rsk) activity is protective against mutant huntingtin toxicity

Molecular Neurodegeneration

Jordi Alberch¹  Esther Pérez-Navarro¹  Ana Saavedra¹  Laura Rué¹  Marta Anglada-Huguet¹  Xavier Xifró² 

[1] Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain;Departament de Ciències Mèdiques, Facultat de Medicina, Universitat de Girona, Spain

关键词: striatum;    R6/1 mouse;    PDK1;    neuroprotection;    knock-in mouse;    Huntington's disease;    ERK;    cell death;   

Others  :  865534
DOI  :  10.1186/1750-1326-6-74

 received in 2011-07-28, accepted in 2011-10-31,  发布年份 2011

【 摘 要 】

Background

The 90-kDa ribosomal S6 kinase (Rsk) family is involved in cell survival. Rsk activation is regulated by sequential phosphorylations controlled by extracellular signal-regulated kinase (ERK) 1/2 and 3-phosphoinositide-dependent protein kinase 1 (PDK1). Altered ERK1/2 and PDK1 phosphorylation have been described in Huntington's disease (HD), characterized by the expression of mutant huntingtin (mhtt) and striatal degeneration. However, the role of Rsk in this neurodegenerative disease remains unknown. Here, we analyzed the protein levels, activity and role of Rsk in in vivo and in vitro HD models.

Results

We observed increased protein levels of Rsk1 and Rsk2 in the striatum of Hdh^Q111/Q111 and R6/1 mice, STHdh^Q111/Q111 cells and striatal cells transfected with full-length mhtt. Analysis of the phosphorylation of Rsk in Hdh mice and STHdh cells showed reduced levels of phospho Ser-380 (dependent on ERK1/2), whereas phosphorylation at Ser-221 (dependent on PDK1) was increased. Moreover, we found that elevated Rsk activity in STHdh^Q111/Q111 cells was mainly due to PDK1 activity, as assessed by transfection with Rsk mutant constructs. The increase of Rsk in STHdh^Q111/Q111 cells occurred in the cytosol and in the nucleus, which results in enhanced phosphorylation of both cytosolic and nuclear Rsk targets. Finally, pharmacological inhibition of Rsk, knock-down and overexpression experiments indicated that Rsk activity exerts a protective effect against mhtt-induced cell death in STHdh^Q7/Q7 cells transfected with mhtt.

Conclusion

The increase of Rsk levels and activity would act as a compensatory mechanism with capacity to prevent mhtt-mediated cell death. We propose Rsk as a good target for neuroprotective therapies in HD.

【 授权许可】

   
2011 Xifró et al; licensee BioMed Central Ltd.

【 图 表 】

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