Disrupted Ca2+ homeostasis contributes to endoplasmic reticulum stress and has been implicated in Huntington disease (HD) pathogenesis. Here, Naranjo et al. report decreased expression of downstream regulatory element antagonist modulator (DREAM) — a member of the potassium channel-interacting protein subfamily of neuronal Ca2+ sensors that is important for Ca2+ homeostasis — in in vitro and in vivo mouse HD models, as well as in postmortem brain samples from patients with HD. This reduction in DREAM was found to be a neuroprotective, leading to derepression of activating transcription factor 6 signalling and activation of the prosurvival unfolded protein response. Chronic administration of the DREAM-binding antidiabetic drug repaglinide blocked DREAM activity in a mouse model of HD, delaying onset of motor dysfunction, reducing striatal atrophy and prolonging life span.
References
Naranjo, J. et al. Activating transcription factor 6 derepression mediates neuroprotection in Huntington disease. J. Clin. Invest. 126, 627–638 (2016)
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Crunkhorn, S. Blocking DREAM delays neurodegeneration. Nat Rev Drug Discov 15, 160 (2016). https://doi.org/10.1038/nrd.2016.37
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DOI: https://doi.org/10.1038/nrd.2016.37