A novel target for Huntington's disease: ERK at the crossroads of signaling. The ERK signaling pathway is implicated in Huntington's disease and its upregulation ameliorates pathology.
A novel target for Huntington's disease: ERK at the crossroads of signaling. The ERK signaling pathway is implicated in Huntington's disease and its upregulation ameliorates pathology.
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DOI：
10.1002/bies.201100116
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发表时间：
2012-02
期刊：
影响因子：
4
通讯作者：
Marsh, J. Lawrence
中科院分区：
文献类型：
--
作者：
Bodai, Laszlo;Marsh, J. Lawrence
Activating the ERK pathway (extracellular signal-regulated kinase pathway) has proven beneficial in several models of Huntington’s disease, and drugs that are protective in HD models have recently been found to activate ERK. Thus, the ERK cascade may be a potential target for therapeutic intervention in this currently untreatable disorder. Huntington’s disease is caused by an expanded polyglutamine repeat in the huntingtin protein that actuates a diverse set of pathogenic mechanisms. In response to mutant huntingtin, ERK is activated and directs a protective transcriptional response and inhibits caspase activation. Paradoxically, Htt also interferes with several signaling events of the ERK pathway. Mutant huntingtin compromises the ERK dependent transcriptional response to corticostriatal BDNF signaling. Mutant huntingtin also hinders glutamate uptake from the synaptic cleft by down-regulating ERK dependent expression of glutamate transporters leaving cells vulnerable to excitotoxicity. Some of this cellular complexity can be capitalized on to achieve selective activation of ERK which can be protective.
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