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Activating transcription factor 6 derepression mediates neuroprotection in Huntington disease
José R. Naranjo, … , Jia-Yi Li, Britt Mellström
José R. Naranjo, … , Jia-Yi Li, Britt Mellström
Published January 11, 2016
Citation Information: J Clin Invest. 2016;126(2):627-638. https://doi.org/10.1172/JCI82670.
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Research Article Neuroscience Article has an altmetric score of 22

Activating transcription factor 6 derepression mediates neuroprotection in Huntington disease

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Abstract

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.

Authors

José R. Naranjo, Hongyu Zhang, Diego Villar, Paz González, Xose M. Dopazo, Javier Morón-Oset, Elena Higueras, Juan C. Oliveros, María D. Arrabal, Angela Prieto, Pilar Cercós, Teresa González, Alicia De la Cruz, Juan Casado-Vela, Alberto Rábano, Carmen Valenzuela, Marta Gutierrez-Rodriguez, Jia-Yi Li, Britt Mellström

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Figure 3

Repaglinide binds to DREAM and blocks DREAM activity on potassium channel gating.

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Repaglinide binds to DREAM and blocks DREAM activity on potassium channe...
(A) Affinity pull-down assay of recombinant GST, GST-DREAM, or GST-neurocalcin (2% input in lanes 1–3). For each recombinant protein, the binding signal is shown to uncoupled Sepharose (lane 4), or to Sepharose coupled to (i) repaglinide with 4 mM EGTA (lane 5) or with 4 mM Ca2+ (lane 6) and (ii) other benzoic acid derivatives (lanes 7–9; cyanic acid, aspirin, and 3,4,5-trimethyoxybenzoic acid, respectively). A representative blot is shown. (B) Surface plasmon resonance analysis of the binding of repaglinide (RP), CL-888, and glibenclamide (Glib) (all at 2 μM) to immobilized GST-DREAM. A representative curve is shown. (C and D) Effects of repaglinide, CL-888, or glibenclamide on Kv4.3 channel gating. (C) Concentration curve for the inhibitory effect of repaglinide or CL-888. Experiments in CHO cells transfected with Kv4.3 and DREAM. Blockade was measured as the reduction in the amount of charge crossing the cell membrane (estimated from the integral of the current signal) during the 250 ms pulses to +60 mV. Lines represent the fit of the data to a Hill equation. Each point represents mean ± SEM of 3 to 9 experiments. (D) Representative Kv4.3+DREAM currents recorded on transiently transfected CHO cells. Current traces were obtained after depolarization to +60 mV from a holding potential of 80 mV. Currents were recorded in control conditions and after perfusion with 5 μM glibenclamide (left), 100 nM CL-888 (center), or 100 nM repaglinide (right).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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