Activating transcription factor 6 derepression mediates neuroprotection in Huntington disease Articles uri icon


  • Naranjo, J.R.
  • Zhang, H.
  • Villar, D.
  • Dopazo, X.M.
  • Morón-Oset, J.
  • Higueras, E.
  • Oliveros, J.C.
  • Arrabal, M.D.
  • Prieto, A.
  • Cercós, P.
  • González, T.
  • De La Cruz, A.
  • Rábano, A.
  • Valenzuela, C.
  • Gutierrez-Rodriguez, M.
  • Li, J.-Y.
  • Mellström, B.

publication date

  • January 2016

start page

  • 627

end page

  • 638


  • 2


  • 126

International Standard Serial Number (ISSN)

  • 0021-9738


  • Deregulated protein and Ca2+ homeostasis underlie synaptic dysfunction and neurodegeneration in Huntington disease (HD); however, the factors that disrupt homeostasis are not fully understood. Here, we determined that expression of downstream regulatory element antagonist modulator (DREAM), a multifunctional Ca2+-binding protein, is reduced in murine in vivo and in vitro HD models and in HD patients. DREAM downregulation was observed early after birth and was associated with endogenous neuroprotection. In the R6/2 mouse HD model, induced DREAM haplodeficiency or blockade of DREAM activity by chronic administration of the drug repaglinide delayed onset of motor dysfunction, reduced striatal atrophy, and prolonged life span. DREAM-related neuroprotection was linked to an interaction between DREAM and the unfolded protein response (UPR) sensor activating transcription factor 6 (ATF6). Repaglinide blocked this interaction and enhanced ATF6 processing and nuclear accumulation of transcriptionally active ATF6, improving prosurvival UPR function in striatal neurons. Together, our results identify a role for DREAM silencing in the activation of ATF6 signaling, which promotes early neuroprotection in HD.


  • activating transcription factor 6 basic leucine zipper transcription factor calsenilin repaglinide shal potassium channel activating transcription factor 6 atf6 protein; human atf6 protein; mouse carbamic acid derivative csen protein; mouse kcnip3 protein; human kv channel interacting protein piperidine derivative repressor protein animal experiment animal model article cell viability controlled study corpus striatum down regulation gene repression human human cell huntington chorea in vitro study mouse neuroprotection nonhuman priority journal protein binding protein expression protein function protein protein interaction signal transduction unfolded protein response animal cho cell line cricetulus disease model genetics hek293 cell line hela cell line huntington chorea metabolism nerve cell pathology signal transduction activating transcription factor 6 animals carbamates cho cells corpus striatum cricetulus disease models; animal hek293 cells hela cells humans huntington disease kv channel-interacting proteins mice neurons piperidines repressor proteins signal transduction