Early postnatal behavioral, cellular, and molecular changes in models of Huntington disease are reversible by HDAC inhibition

Siebzehnrübl, Florian A.; Raber, Kerstin; Urbach, Yvonne K.; Schulze-Krebs, Anja; Canneva, Fabio; Moceri, Sandra; Habermeyer, Johanna; Achoui, Dalila; Gupta, Bhavana; Steindler, Dennis A.; Stephan, Michael; Nguyen, Huu Phuc; Bonin, Michael; Rieß, Olaf; Bauer, Andreas; Aigner, Ludwig; Couillard‐Després, Sébastien; Paucar, Martin; Svenningsson, Per; Osmand, Alexander P.; Andreew, Alexander; Zabel, Claus; Weiss, Andreas; Kühn, Rainer; Moussaoui, Saliha; Blockx, Ines; Linden, Annemie Van der; Cheong, Rachel Y.; Roybon, Laurent; Petersén, Åsa; Hörsten, Stephan von

doi:10.1073/pnas.1807962115

Cited by 53 publications

(49 citation statements)

References 92 publications

(119 reference statements)

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“…Furthermore, genetic mutation or knockdown of Hdac2 in the central nervous system improved spatial, associative, and threat recognition memory in mouse models of Pitt-Hopkins syndrome (Tcf4 +/-) (17) and Alzheimer's disease (CK-p25) (18,19). Encouragingly, small molecule HDAC inhibitors conferred cognitive benefits in rodent models of aging (20,21), neurodegeneration (6,(21)(22)(23)(24)(25)(26), and neuropsychiatric (27)(28)(29)(30)(31)(32)(33)(34) disease. Taken together with observations of aberrant HDAC levels in postmortem human brain tissue from donors with Alzheimer's disease (18,19,35), SCZ (29,(36)(37)(38)(39)(40), depression (28,37), and bipolar disorder (39), these findings suggest that HDAC-related mechanisms may play a fundamental role in human cognition.…”

Section: Resultsmentioning

confidence: 99%

PET neuroimaging reveals histone deacetylase dysregulation in schizophrenia

Gilbert¹,

Zürcher²,

Wu³

et al. 2018

Journal of Clinical Investigation

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BACKGROUND.Patients with schizophrenia (SCZ) experience chronic cognitive deficits. Histone deacetylases (HDACs) are enzymes that regulate cognitive circuitry; however, the role of HDACs in cognitive disorders, including SCZ, remains unknown in humans. We previously determined that HDAC2 mRNA levels were lower in dorsolateral prefrontal cortex (DLPFC) tissue from donors with SCZ compared with controls. Here we investigated the relationship between in vivo HDAC expression and cognitive impairment in patients with SCZ and matched healthy controls using [ 11 C]Martinostat positron emission tomography (PET). METHODS.In a case-control study, relative [ 11 C]Martinostat uptake was compared between 14 patients with SCZ or schizoaffective disorder (SCZ/SAD) and 17 controls using hypothesis-driven region-of-interest analysis and unbiased whole brain voxel-wise approaches. Clinical measures, including the MATRICS consensus cognitive battery, were administered. RESULTS.Relative HDAC expression was lower in the DLPFC of patients with SCZ/SAD compared with controls, and HDAC expression positively correlated with cognitive performance scores across groups. Patients with SCZ/SAD also showed lower relative HDAC expression in the dorsomedial prefrontal cortex and orbitofrontal gyrus, and higher relative HDAC expression in the cerebral white matter, pons, and cerebellum compared with controls.CONCLUSIONS. These findings provide in vivo evidence of HDAC dysregulation in patients with SCZ and suggest that altered HDAC expression may impact cognitive function in humans.The severity of cognitive deficits strongly impacts functional outcomes including quality of life (45,46). Thus, amelioration of this highly debilitating form of cognitive impairment represents an important unmet need for SCZ treatment (46).We find that patients with SCZ/schizoaffective disorder (SAD) show differential [ 11 C]Martinostat brain uptake patterns compared with healthy controls, and regional [ 11 C]Martinostat brain uptake correlates with cognitive performance scores.

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Section: Resultsmentioning

confidence: 99%

PET neuroimaging reveals histone deacetylase dysregulation in schizophrenia

Gilbert¹,

Zürcher²,

Wu³

et al. 2018

Journal of Clinical Investigation

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“…Previous studies showed that HDAC3 was a class I histone deacetylase [39]. Histone deacetylase inhibition has a neuro-protective effect via reducing neuroinflammation [33], reported to be beneficial with respect to neurological functions in many diseases, including Alzheimer's disease [40], Huntington's disease [41], TBI, stroke [42], and spinal cord injury [33]. Recent studies reported that HDCA3 inhibition appears to suppress NF-κB transcriptional activity by maintaining the NF-κB p65 acetylated (inactive) state and restraining the inflammatory response [33,43].…”

Section: Discussionmentioning

confidence: 99%

Systemic exosomal miR-193b-3p delivery attenuates neuroinflammation in early brain injury after subarachnoid hemorrhage in mice

Lai

Liang

et al. 2020

J Neuroinflammation

140

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Background: Inflammation is a potential crucial factor in the pathogenesis of subarachnoid hemorrhage (SAH). Circulating microRNAs (miRNAs) are involved in the regulation of diverse aspects of neuronal dysfunction. The therapeutic potential of miRNAs has been demonstrated in several CNS disorders and is thought to involve modulation of neuroinflammation. Here, we found that peripherally injected modified exosomes (Exos) delivered miRNAs to the brains of mice with SAH and that the potential mechanism was regulated by regulation of neuroinflammation. Methods: Next-generation sequencing (NGS) and qRT-PCR were used to define the global miRNA profile of plasma exosomes in aSAH patients and healthy controls. We peripherally injected RVG/Exos/miR-193b-3p to achieve delivery of miR-193b-3p to the brain of mice with SAH. The effects of miR-193b-3p on SAH were assayed using a neurological score, brain water content, blood-brain barrier (BBB) injury, and Fluoro-Jade C (FJC) staining. Western blotting analysis, enzyme-linked immunosorbent assay (ELISA), and qRT-PCR were used to measure various proteins and mRNA levels. Results: NGS and qRT-PCR revealed that four circulating exosomal miRNAs were differentially expressed. RVG/Exos exhibited improved targeting to the brains of SAH mice. MiR-193b-3p suppressed the expression and activity of HDAC3, upregulating the acetylation of NF-κB p65. Finally, miR-193b-3p treatment mitigated the neurological behavioral impairment, brain edema, BBB injury, and neurodegeneration induced by SAH, and reduced inflammatory cytokine expression in the brains of mice after SAH. Conclusions: Exos/miR-193b-3p treatment attenuated the inflammatory response by acetylation of the NF-κB p65 via suppressed expression and activity of HDAC3. These effects alleviated neurobehavioral impairments and neuroinflammation following SAH.

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“…We show that Nmnat can improve behavioral and survival phenotypes in HD even when induced at advanced disease stages. This will be clinically beneficial, as most therapeutic interventions are only effective in premanifest disease stages of HD when mild symptoms may be reversible, whereas disease progression becomes faster and relatively resistant to treatment when the symptoms have been fully developed (72). The observed reduction of NMNAT transcript level detected in human HD brains, typically in the caudate nucleus region (73), indicates that compromised Nmnat function may correlate with increased susceptibility to HD.…”

Section: Discussionmentioning

confidence: 99%

Nmnat restores neuronal integrity by neutralizing mutant Huntingtin aggregate-induced progressive toxicity

Tao

Brazill

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Accumulative aggregation of mutant Huntingtin (Htt) is a primary neuropathological hallmark of Huntington’s disease (HD). Currently, mechanistic understanding of the cytotoxicity of mutant Htt aggregates remains limited, and neuroprotective strategies combating mutant Htt-induced neurodegeneration are lacking. Here, we show that in Drosophila models of HD, neuronal compartment-specific accumulation of mutant Htt aggregates causes neurodegenerative phenotypes. In addition to the increase in the number and size, we discovered an age-dependent acquisition of thioflavin S+, amyloid-like adhesive properties of mutant Htt aggregates and a concomitant progressive clustering of aggregates with mitochondria and synaptic proteins, indicating that the amyloid-like adhesive property underlies the neurotoxicity of mutant Htt aggregation. Importantly, nicotinamide mononucleotide adenylyltransferase (NMNAT), an evolutionarily conserved nicotinamide adenine dinucleotide (NAD+) synthase and neuroprotective factor, significantly mitigates mutant Htt-induced neurodegeneration by reducing mutant Htt aggregation through promoting autophagic clearance. Additionally, Nmnat overexpression reduces progressive accumulation of amyloid-like Htt aggregates, neutralizes adhesiveness, and inhibits the clustering of mutant Htt with mitochondria and synaptic proteins, thereby restoring neuronal function. Conversely, partial loss of endogenous Nmnat exacerbates mutant Htt-induced neurodegeneration through enhancing mutant Htt aggregation and adhesive property. Finally, conditional expression of Nmnat after the onset of degenerative phenotypes significantly delays the progression of neurodegeneration, revealing the therapeutic potential of Nmnat-mediated neuroprotection at advanced stages of HD. Our study uncovers essential mechanistic insights to the neurotoxicity of mutant Htt aggregation and describes the molecular basis of Nmnat-mediated neuroprotection in HD.

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Early postnatal behavioral, cellular, and molecular changes in models of Huntington disease are reversible by HDAC inhibition

Cited by 53 publications

References 92 publications

PET neuroimaging reveals histone deacetylase dysregulation in schizophrenia

PET neuroimaging reveals histone deacetylase dysregulation in schizophrenia

Systemic exosomal miR-193b-3p delivery attenuates neuroinflammation in early brain injury after subarachnoid hemorrhage in mice

Nmnat restores neuronal integrity by neutralizing mutant Huntingtin aggregate-induced progressive toxicity

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