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

Authors

  • László Bodai,

    Corresponding author
    1. Department of Biochemistry and Molecular Biology, University of Szeged, Szeged, Hungary
    • Department of Biochemistry and Molecular Biology, University of Szeged, Szeged, Hungary.
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  • J. Lawrence Marsh

    Corresponding author
    1. Department of Developmental and Cell Biology, University of California Irvine, Irvine, CA, USA
    2. Department of Pathology, University of California Irvine, Irvine, CA, USA
    3. Developmental Biology Center, University of California Irvine, Irvine, CA, USA
    • Department of Developmental and Cell Biology, University of California Irvine, Irvine, CA, USA.
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Abstract

Activating the ERK pathway (extracellular signal-regulated kinase pathway) has proven beneficial in several models of Huntington's disease (HD), 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. HD is caused by an expanded polyglutamine repeat in the huntingtin (Htt) protein that actuates a diverse set of pathogenic mechanisms. In response to mutant Htt, 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 Htt compromises the ERK-dependent transcriptional response to corticostriatal BDNF signaling. Mutant Htt 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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