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.

Dietary n−3 polyunsaturated fatty acids (PUFAs) have been reported to exhibit antiarrhythmic properties, and these effects have been attributed to their capability to modulate ion channels. In the present review, we will focus on the effects of PUFAs on a cardiac sodium channel (Nav1.5) and two potassium channels involved in cardiac atrial and ventricular repolarization (Kv) (Kv1.5 and Kv11.1). n−3 PUFAs of marine (docosahexaenoic, DHA and eicosapentaenoic acid, EPA) and plant origin (alpha-linolenic acid, ALA) block Kv1.5 and Kv11.1 channels at physiological concentrations. Moreover, DHA and EPA decrease the expression levels of Kv1.5, whereas ALA does not. DHA and EPA also decrease the magnitude of the currents elicited by the activation of Nav1.5 and calcium channels. These effects on sodium and calcium channels should theoretically shorten the cardiac action potential duration (APD), whereas the blocking actions of n−3 PUFAs on Kv channels would be expected to produce a lengthening of cardiac action potential. Indeed, the effects of n−3 PUFAs on the cardiac APD and, therefore, on cardiac arrhythmias vary depending on the method of application, the animal model, and the underlying cardiac pathology.

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Polyunsaturated fatty acids (PUFAs) have been reported to exhibit antiarrhythmic properties, which are attributed to their capability to modulate ion channels. This PUFAs ability has been reported to be due to their effects on the gating properties of ion channels. In the present review, we will focus on the role of PUFAs on the gating of two Kv channels, Kv1.5 and Kv11.1. Kv1.5 channels are blocked by n−3 PUFAs of marine [docosahexaenoic acid (DHA) and eicosapentaenoic acid] and plant origin (alpha-linolenic acid, ALA) at physiological concentrations. The blockade of Kv1.5 channels by PUFAs steeply increased in the range of membrane potentials coinciding with those of Kv1.5 channel activation, suggesting that PUFAs-channel binding may derive a significant fraction of its voltage sensitivity through the coupling to channel gating. A similar shift in the activation voltage was noted for the effects of n–6 arachidonic acid (AA) and DHA on Kv1.1, Kv1.2, and Kv11.1 channels. PUFAs-Kv1.5 channel interaction is time-dependent, producing a fast decay of the current upon depolarization. Thus, Kv1.5 channel opening is a prerequisite for the PUFA-channel interaction. Similar to the Kv1.5 channels, the blockade of Kv11.1 channels by AA and DHA steeply increased in the range of membrane potentials that coincided with the range of Kv11.1 channel activation, suggesting that the PUFAs-Kv channel interactions are also coupled to channel gating. Furthermore, AA regulates the inactivation process in other Kv channels, introducing a fast voltage-dependent inactivation in non-inactivating Kv channels. These results have been explained within the framework that AA closes voltage-dependent potassium channels by inducing conformational changes in the selectivity filter, suggesting that Kv channel gating is lipid dependent.