HDAC4: a key factor underlying brain developmental alterations in CDKL5 disorder

Trazzi, Stefania; Fuchs, Claudia; Viggiano, Rocchina; Franceschi, Marianna De; Valli, Emanuele; Jedynak, Paulina; Hansen, Finn K.; Perini, Giovanni; Rimondini, Roberto; Kurz, Thomas; Bartesaghi, Renata; Ciani, Elisabetta

doi:10.1093/hmg/ddw231

Cited by 85 publications

(96 citation statements)

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“…Using a Cdkl5 KO mouse model, we recently showed that CDKL5 plays a fundamental role in postnatal https://www.sciencedirect.com/topics/neuroscience/hippocampus development, affecting neural precursor proliferation as well as the survival of newborn granule cells . In addition, Cdkl5 deficiency impairs morphogenesis and dendritic arborization of hippocampal neurons and their synaptic connectivity . Spontaneous synaptic activity is impaired in hippocampal slices of a forebrain excitatory neuron specific to Cdkl5 KO mice [Nex‐cKO; ], and excitatory synaptic transmission is reduced in mouse hippocampal cultures silenced for Cdkl5 .…”

Section: Introductionmentioning

confidence: 99%

CDKL5 deficiency predisposes neurons to cell death through the deregulation of SMAD3 signaling

et al. 2019

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CDKL5 deficiency disorder (CDD) is a rare encephalopathy characterized by early onset epilepsy and severe intellectual disability. CDD is caused by mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5 ) gene, a member of a highly conserved family of serine-threonine kinases. Only a few physiological substrates of CDKL5 are currently known, which hampers the discovery of therapeutic strategies for CDD. Here, we show that SMAD3, a primary mediator of TGF-β action, is a direct phosphorylation target of CDKL5 and that CDKL5-dependent phosphorylation promotes SMAD3 protein stability. Importantly, we found that restoration of the SMAD3 signaling through TGF-β1 treatment normalized defective neuronal survival and maturation in Cdkl5 knockout (KO) neurons. Moreover, we demonstrate that Cdkl5 KO neurons are more vulnerable to neurotoxic/excitotoxic stimuli. In vivo treatment with TGF-β1 prevents increased NMDA-induced cell death in hippocampal neurons from Cdkl5 KO mice, suggesting an involvement of the SMAD3 signaling deregulation in the neuronal susceptibility to excitotoxic injury of Cdkl5 KO mice. Our finding reveals a new function for CDKL5 in maintaining neuronal survival that could have important implications for susceptibility to neurodegeneration in patients with CDD.Brain Pathology 29 (2019) 658-674

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Section: Introductionmentioning

confidence: 99%

CDKL5 deficiency predisposes neurons to cell death through the deregulation of SMAD3 signaling

et al. 2019

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“…d ). Furthermore, two specific HDAC4 inhibitors, namely, LMK235 and Tasquinimod, suppressed MKK7 mRNA and protein levels in a dose‐dependent manner and consequently resulted in a reduction in the activities of JNK/c‐Jun (Figs. e and 2 f ).…”

Section: Resultsmentioning

confidence: 99%

MKK7 transcription positively or negatively regulated by SP1 and KLF5 depends on HDAC4 activity in glioma

Wang

Xia

et al. 2019

Intl Journal of Cancer

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JNK activity has been implicated in the malignant proliferation, invasion and drug‐resistance of glioma cells (GCs), but the molecular mechanisms underlying JNK activation are currently unknown. Here, we reported that MKK7, not MKK4, directly activates JNK in GCs and exerts oncogenic effects on tumor formation. Notably, MKK7 expression in glioma tissues was closely correlated with the grade of the glioma and JNK/c‐Jun activation. Mechanistically, MKK7 transcription critically depends on the complexes formed by HDAC4 and the transcriptional factors SP1 and Krüppel‐like factor‐5 (KLF5), wherein HDAC4 directly deacetylates both SP1 and KLF5 and synergistically upregulates MKK7 transcription through two SP1 sites located on its promoter. In contrast, the increases in acetylated‐SP1 and acetylated‐KLF5 after HDAC4 inhibition switched to transcriptionally suppress MKK7. Selective inhibition of HDAC4 by LMK235, siRNAs or blockage of SP1 and KLF5 by the ectopic dominant‐negative SP1 greatly reduced the malignant capacity of GCs. Furthermore, suppression of both MKK7 expression and JNK/c‐Jun activities was involved in the tumor‐growth inhibitory effects induced by LMK235 in U87‐xenograft mice. Interestingly, HDAC4 is highly expressed in glioma tissues, and the rate of HDAC4 nuclear import is closely correlated with glioma grade, as well as with MKK7 expression. Collectively, these findings demonstrated that highly expressed MKK7 contributes to JNK/c‐Jun signaling‐mediated glioma formation. MKK7 transcription, regulated by SP1 and KLF5, critically depends on HDAC4 activity, and inhibition of HDAC4 presents a potential strategy for suppressing the oncogenic roles of MKK7/JNK/c‐Jun signaling in GCs.

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“…Although Hdac4 was selected as a target based on transcriptomic data from female mice, the compound reduced ethanol drinking in both male and female mice. Others have shown that HDAC4 is regulated by neuronal activity and plasticity, and inhibiting HDAC4 via LMK 235 can alter neuronal morphology [50,65,66]. Ongoing work is focused on using this data to identify and test compounds with high clinical translational potential.…”

Section: Pharmacologically Targeting Hdac4 To Reduce Binge-like Drinkingmentioning

confidence: 99%

Chronic Chemogenetic Stimulation of the Nucleus Accumbens Produces Lasting Reductions in Binge Drinking and Ameliorates Alcohol-Related Morphological and Transcriptional Changes

et al. 2020

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Binge drinking is a dangerous pattern of behavior. We tested whether chronically manipulating nucleus accumbens (NAc) activity (via clozapine-N-oxide (CNO) and Designer Receptors Exclusively Activated by Designer Drugs (DREADD)) could produce lasting effects on ethanol binge-like drinking in mice selectively bred to drink to intoxication. We found chronically increasing NAc activity (4 weeks, via CNO and the excitatory DREADD, hM3Dq) decreased binge-like drinking, but did not observe CNO-induced changes in drinking with the inhibitory DREADD, hM4Di. The CNO/hM3Dq-induced reduction in ethanol drinking persisted for at least one week, suggesting adaptive neuroplasticity via transcriptional and epigenetic mechanisms. Therefore, we defined this plasticity at the morphological and transcriptomic levels. We found that chronic binge drinking (6 weeks) altered neuronal morphology in the NAc, an effect that was ameliorated with CNO/hM3Dq. Moreover, we detected significant changes in expression of several plasticity-related genes with binge drinking that were ameliorated with CNO treatment (e.g., Hdac4). Lastly, we found that LMK235, an HDAC4/5 inhibitor, reduced binge-like drinking. Thus, we were able to target specific molecular pathways using pharmacology to mimic the behavioral effects of DREADDs.Brain Sci. 2020, 10, 109 2 of 22 (DID) paradigm, mice are offered an ethanol solution early into the active period of their circadian cycle and can achieve BALs >80 mg%, suggesting they drink to intoxication [1]. C57BL/6J mice are typically reported as high drinking and can achieve BALs >80mg% in the DID paradigm; however, significant inbred strain differences have been observed suggesting there exists a genetic contribution to this phenotype [2,3]. The DID assay was used to independently create two lines of mice, HDID-1 and HDID-2, that were selectively bred (from genetically heterogeneous HS/Npt progenitors) for high BALs after DID [4,5]. HDID and HS/Npt mice have been extensively characterized and HDID mice represent a unique genetic animal model of risk for drinking to intoxication [6][7][8][9][10][11][12][13][14]. FDA approved compounds for treatment of AUD, as well as several investigational compounds, have been tested for efficacy in reducing binge-like drinking using the DID paradigm in C57BL/6J and HDID mice, as well as other genotypes, with mixed results [15][16][17][18][19][20]. Together, the results of these studies suggest that testing potential therapies in more than one inbred strain may represent a more beneficial strategy for clinical translation.Koob and Volkow (2010) reviewed decades of clinical and pre-clinical studies to address the neural circuitry associated with the three stages of the addiction cycle: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation [21]. The nucleus accumbens (NAc) is identified as an important region for each of these three stages. There is also extensive evidence that altering activity in the NAc reduces alcohol drinking, craving, and relapse. To achiev...

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HDAC4: a key factor underlying brain developmental alterations in CDKL5 disorder

Cited by 85 publications

References 61 publications

CDKL5 deficiency predisposes neurons to cell death through the deregulation of SMAD3 signaling

CDKL5 deficiency predisposes neurons to cell death through the deregulation of SMAD3 signaling

MKK7 transcription positively or negatively regulated by SP1 and KLF5 depends on HDAC4 activity in glioma

Chronic Chemogenetic Stimulation of the Nucleus Accumbens Produces Lasting Reductions in Binge Drinking and Ameliorates Alcohol-Related Morphological and Transcriptional Changes

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