Inhibition of DREAM-ATF6 interaction delays onset of cognition deficit in a mouse model of Huntington’s disease

López-Hurtado, Alejandro; Burgos, Daniel F; González, Paz; Dopazo, Xosé M.; González, Valentina; Rábano, Alberto; Mellström, Britt; Naranjo, José R.

doi:10.1186/s13041-018-0359-6

Cited by 19 publications

(35 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Outside the nucleus, DREAM interacts with presenilins to modulate calcium release from the endoplasmic reticulum (Lilliehook et al, 2002). Additionally, the role of the downregulation of DREAM as part of an endogenous neuroprotective mechanism that improves ATF6 processing, neuronal survival in the striatum, and motor coordination in R6/2 mice, a model of Huntington’s disease (HD), has been recently described (Naranjo et al, 2016; López-Hurtado et al, 2018). Besides, DREAM acts as a regulatory subunit of K V 4.3 channels by inducing: (i) increased traffic of K V 4.3 channels to the membrane; (ii) delayed inactivation kinetics; and (iii) accelerated activation and recovery kinetics from inactivation of K V 4.3 channels (An et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Identification of IQM-266, a Novel DREAM Ligand That Modulates KV4 Currents

Peraza

Cercós

Miaja

et al. 2019

Front. Mol. Neurosci.

Self Cite

View full text Add to dashboard Cite

Downstream Regulatory Element Antagonist Modulator (DREAM)/KChIP3/calsenilin is a neuronal calcium sensor (NCS) with multiple functions, including the regulation of A-type outward potassium currents (IA). This effect is mediated by the interaction between DREAM and KV4 potassium channels and it has been shown that small molecules that bind to DREAM modify channel function. A-type outward potassium current (IA) is responsible of the fast repolarization of neuron action potentials and frequency of firing. Using surface plasmon resonance (SPR) assays and electrophysiological recordings of KV4.3/DREAM channels, we have identified IQM-266 as a DREAM ligand. IQM-266 inhibited the KV4.3/DREAM current in a concentration-, voltage-, and time-dependent-manner. By decreasing the peak current and slowing the inactivation kinetics, IQM-266 led to an increase in the transmembrane charge (QKV4.3/DREAM) at a certain range of concentrations. The slowing of the recovery process and the increase of the inactivation from the closed-state inactivation degree are consistent with a preferential binding of IQM-266 to a pre-activated closed state of KV4.3/DREAM channels. Finally, in rat dorsal root ganglion neurons, IQM-266 inhibited the peak amplitude and slowed the inactivation of IA. Overall, the results presented here identify IQM-266 as a new chemical tool that might allow a better understanding of DREAM physiological role as well as modulation of neuronal IA in pathological processes.

show abstract

Section: Introductionmentioning

confidence: 99%

Identification of IQM-266, a Novel DREAM Ligand That Modulates KV4 Currents

Peraza

Cercós

Miaja

et al. 2019

Front. Mol. Neurosci.

Self Cite

View full text Add to dashboard Cite

show abstract

“…These results confirm the Ca 2+ -independent nature of this interaction, as previously described (Buxbaum et al, 1998; Fedrizzi et al, 2008). Then, we proceeded to investigate a potential blockage of the DREAM-PS2 interaction by the DREAM binding molecule repaglinide, known to affect the interaction of DREAM with other proteins including Kv4 potassium channels and ATF6 (Naranjo et al, 2016; López-Hurtado et al, 2018). In vitro exposure to repaglinide significantly reduced the Myc-DREAM/Flag-Ct-PS2 coimmunoprecipitation (Figure 3C).…”

Section: Resultsmentioning

confidence: 99%

“…In previous work, we have shown that reduction in DREAM protein levels or blockade of DREAM activity, using repaglinide, activates ATF6 processing which results in a neuroprotective effect in murine models of Huntington’s disease, delaying the onset and the progression of motor and cognitive decline in these mice (Naranjo et al, 2016; López-Hurtado et al, 2018). This finding opened a new avenue toward the search for effective HD treatments.…”

Section: Discussionmentioning

confidence: 98%

See 1 more Smart Citation

Inhibition of the Neuronal Calcium Sensor DREAM Modulates Presenilin-2 Endoproteolysis

Naranjo

González

López-Hurtado

et al. 2018

Front. Mol. Neurosci.

Self Cite

View full text Add to dashboard Cite

Deregulated intracellular Ca2+ and protein homeostasis underlie synaptic dysfunction and are common features in neurodegenerative diseases. DREAM, also known as calsenilin or KChIP-3, is a multifunctional Ca2+ binding protein of the neuronal calcium sensor superfamily with specific functions through protein-DNA and protein-protein interactions. Small-molecules able to bind DREAM, like the anti-diabetic drug repaglinide, disrupt some of the interactions with other proteins and modulate DREAM activity on Kv4 channels or on the processing of activating transcription factor 6 (ATF6). Here, we show the interaction of endogenous DREAM and presenilin-2 (PS2) in mouse brain and, using DREAM deficient mice or transgenic mice overexpressing a dominant active DREAM (daDREAM) mutant in the brain, we provide genetic evidence of the role of DREAM in the endoproteolysis of endogenous PS2. We show that repaglinide disrupts the interaction between DREAM and the C-terminal PS2 fragment (Ct-PS2) by coimmunoprecipitation assays. Exposure to sub-micromolar concentrations of repaglinide reduces the levels of Ct-PS2 fragment in N2a neuroblastoma cells. These results suggest that the interaction between DREAM and PS2 may represent a new target for modulation of PS2 processing, which could have therapeutic potential in Alzheimer’s disease (AD) treatment.

show abstract

“…These observations in both photoreceptors and spinal neurons, suggest that modifying ATF6 activity could be a therapeutic approach to mitigate neurodegenerative diseases. Indeed, de-repression of Atf6 in a mouse model of Huntington’s disease provides neuroprotection to both striatal and hippocampal neurons (López-Hurtado et al, 2018; Naranjo et al, 2016). Furthermore, a small molecule activator of ATF6 reduces amyloidogenic protein secretion and aggregation, providing additional justification for targeting the ATF6 pathway in neurodegenerative disease (Plate et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Establishment and validation of an endoplasmic reticulum stress reporter to monitor zebrafish ATF6 activity in development and disease

Clark

Nonarath

Bostrom

et al. 2019

Preprint

View full text Add to dashboard Cite

Statement: We have established and validated transgenic zebrafish reporter lines to 13 quantitatively measure the ATF6 branch of the endoplasmic reticulum stress pathway in 14 development and disease. 15 16 Abstract 17Induction of endoplasmic reticulum (ER) stress is associated with diverse developmental 18 and degenerative diseases. Modified ER homeostasis causes activation of conserved stress 19 pathways at the ER called the unfolded protein response (UPR). ATF6 is a transcription factor 20 activated during ER stress as part of a coordinated UPR. ATF6 resides at the ER, and upon 21 activation is transported to the Golgi apparatus where it is cleaved by proteases to create an 22 amino-terminal cytoplasmic fragment (ATF6f). ATF6f translocates to the nucleus to activate 23 transcriptional targets. Here, we describe establishment and validation of zebrafish reporter lines 24 for ATF6 activity. These transgenic lines are based on a defined and multimerized ATF6 25 consensus site which drives either eGFP or destabilized eGFP (d2GFP), enabling dynamic study 26 of ATF6 activity during development and disease. The results show that the reporter is specific 27 for the ATF6 pathway, active during development, and induced in disease models known to 28 engage UPR. Specifically, during development, ATF6 activity is highest in the lens, skeletal 29 muscle, fins, and gills. The reporter is also activated by common chemical inducers of ER stress 30 including tunicamycin, thapsigargin, and brefeldin A, as well as by heat shock. In both an ALS 31 and a cone dystrophy model, ATF6 reporter expression is induced in spinal cord interneurons or 32 photoreceptors, respectively, suggesting a role for ATF6 response in multiple neurodegenerative 33 diseases. Collectively our results show these ATF6 reporters can be used to monitor ATF6 34 activity changes throughout development and in zebrafish models of disease. 35 36 37

show abstract

Inhibition of DREAM-ATF6 interaction delays onset of cognition deficit in a mouse model of Huntington’s disease

Cited by 19 publications

References 55 publications

Identification of IQM-266, a Novel DREAM Ligand That Modulates KV4 Currents

Identification of IQM-266, a Novel DREAM Ligand That Modulates KV4 Currents

Inhibition of the Neuronal Calcium Sensor DREAM Modulates Presenilin-2 Endoproteolysis

Establishment and validation of an endoplasmic reticulum stress reporter to monitor zebrafish ATF6 activity in development and disease

Contact Info

Product

Resources

About