Haploinsufficiency of CYP8B1 associates with increased insulin sensitivity in humans

10.1172/JCI152961The Journal of clinical investigation13221e152961

Ermin deficiency leads to compromised myelin, inflammatory milieu, and susceptibility to demyelinating insult

Ermin is an actin-binding protein found almost exclusively in the central nervous system (CNS) as a component of myelin sheaths. Although Ermin has been predicted to play a role in the formation and stability of myelin sheaths, this has not been directly examined in vivo. Here, we show that Ermin is essential for myelin sheath integrity and normal saltatory conduction. Loss of Ermin in mice caused de-compacted and fragmented myelin sheaths and led to slower conduction along with progressive neurological deficits. RNA sequencing of the corpus callosum, the largest white matter structure in the CNS, pointed to inflammatory activation in aged Ermin-deficient mice, which was corroborated by increased levels of microgliosis and astrogliosis. The inflammatory milieu and myelin abnormalities were further associated with increased susceptibility to immune-mediated demyelination insult in Ermin knockout mice. Supporting a possible role of Ermin deficiency in inflammatory white matter disorders, a rare inactivating mutation in the ERMN gene was identified in multiple sclerosis patients. Our findings demonstrate a critical role for Ermin in maintaining myelin integrity. Given its near-exclusive expression in myelinating oligodendrocytes, Ermin deficiency represents a compelling “inside-out” model of inflammatory dysmyelination and may offer a new paradigm for the development of myelin stability-targeted therapies

Treatment with the MAO-A inhibitor clorgyline elevates monoamine neurotransmitter levels and improves affective phenotypes in a mouse model of Huntington disease

10.1016/j.expneurol.2016.01.019EXPERIMENTAL NEUROLOGY2784-Oc

Connectomic imaging reveals Huntington-related pathological and pharmaceutical effects in a mouse model

Recent studies suggest that neurodegenerative diseases could affect brain structure and function in disease-specific network patterns; however, how spontaneous activity affects structural covariance network (SC) is not clear. We hypothesized that hyper-excitability in Huntington disease (HD) disrupts the coordinated structural and functional connectivity, and treatment with memantine helps to reduce excitotoxicity and normalize the connectivity. MRI was conducted to measure somatosensory activation, resting-state functional-connectivity (rsFC), SC, amplitude of low frequency fluctuation (ALFF) and ALFF covariance (ALFFC) in the YAC128 mouse model of HD. We found somatosensory activation was unchanged but the subcortical ALFF was increased in HD mice, indicating subcortical but not cortical hyperactivity. The reduced sensorimotor rsFC but spared hippocampal and default mode networks in the HD mice was consistent with the more pronounced impairment in motor function compared with cognitive performance. The disease suppressed SC globally and reduced ALFFC in the basal ganglia network as well as its anti-correlation with the default mode network. By comparing these connectivity measures, we found that the originally coupled rsFC-SC relationship was impaired whereas SC-ALFFC correlation was increased by HD, suggesting disease facilitated covariation of brain volume and activity amplitude but not neural synchrony. The comparison with mono-synaptic axonal projection supports the hypothesis that rsFC, but not SC or ALFFC, is highly dependent on structural connectivity under healthy conditions. Treatment with memantine had a strong effect on normalizing the SC and reducing ALFF while slightly increasing other connectivity measures and restoring the rsFC-SC coupling, which is consistent with its effect on alleviating hyper-excitability and improving the coordinated neural growth. These results indicate that HD affects the cerebral structure–function relationship which could be partially reverted by NMDA antagonism. These connectivity measures provide unique insights into pathological and pharmaceutical effects in brain circuitry, and could be translatable biomarkers for evaluating drug effect and refining its efficacy

Large-scale transcriptomic analysis reveals that pridopidine reverses aberrant gene expression and activates neuroprotective pathways in the YAC128 HD mouse

Abstract Background Huntington Disease (HD) is an incurable autosomal dominant neurodegenerative disorder driven by an expansion repeat giving rise to the mutant huntingtin protein (mHtt), which is known to disrupt a multitude of transcriptional pathways. Pridopidine, a small molecule in development for treatment of HD, has been shown to improve motor symptoms in HD patients. In HD animal models, pridopidine exerts neuroprotective effects and improves behavioral and motor functions. Pridopidine binds primarily to the sigma-1 receptor, (IC50 ~ 100 nM), which mediates its neuroprotective properties, such as rescue of spine density and aberrant calcium signaling in HD neuronal cultures. Pridopidine enhances brain-derived neurotrophic factor (BDNF) secretion, which is blocked by putative sigma-1 receptor antagonist NE-100, and was shown to upregulate transcription of genes in the BDNF, glucocorticoid receptor (GR), and dopamine D1 receptor (D1R) pathways in the rat striatum. The impact of different doses of pridopidine on gene expression and transcript splicing in HD across relevant brain regions was explored, utilizing the YAC128 HD mouse model, which carries the entire human mHtt gene containing 128 CAG repeats. Methods RNAseq was analyzed from striatum, cortex, and hippocampus of wild-type and YAC128 mice treated with vehicle, 10 mg/kg or 30 mg/kg pridopidine from the presymptomatic stage (1.5 months of age) until 11.5 months of age in which mice exhibit progressive disease phenotypes. Results The most pronounced transcriptional effect of pridopidine at both doses was observed in the striatum with minimal effects in other regions. In addition, for the first time pridopidine was found to have a dose-dependent impact on alternative exon and junction usage, a regulatory mechanism known to be impaired in HD. In the striatum of YAC128 HD mice, pridopidine treatment initiation prior to symptomatic manifestation rescues the impaired expression of the BDNF, GR, D1R and cAMP pathways. Conclusions Pridopidine has broad effects on restoring transcriptomic disturbances in the striatum, particularly involving synaptic transmission and activating neuroprotective pathways that are disturbed in HD. Benefits of treatment initiation at early disease stages track with trends observed in the clinic

Laquinimod rescues striatal, cortical and white matter pathology and results in modest behavioural improvements in the YAC128 model of Huntington disease

Increasing evidence supports a role for abnormal immune activation and inflammatory responses in Huntington disease (HD). In this study, we evaluated the therapeutic potential of laquinimod (1 and 10 mg/kg), a novel immunomodulatory agent shown to be protective in a number of neuroinflammatory conditions, in the YAC128 mouse model of HD. Treatment with laquinimod for 6 months rescued atrophy in the striatum, in certain cortical regions, and in the corpus callosum of YAC128 HD mice. Diffusion tensor imaging showed that white matter microstructural abnormalities in the posterior corpus callosum were improved following treatment with low dose (1 mg/kg) laquinimod, and were paralleled by reduced levels of interleukin-6 in the periphery of YAC128 HD mice. Functionally, treatment with laquinimod (1 and 10 mg/kg) led to modest improvements in motor function and in depressive-like behaviour. Taken together, these results suggest that laquinimod may improve some features of pathology in HD, and provides support for the role of immune activation in the pathogenesis of HD

Structural and molecular myelination deficits occur prior to neuronal loss in the YAC128 and BACHD models of Huntington disease

White matter (WM) atrophy is a significant feature of Huntington disease (HD), although its aetiology and early pathological manifestations remain poorly defined. In this study, we aimed to characterize WM-related features in the transgenic YAC128 and BACHD models of HD. Using diffusion tensor magnetic resonance imaging (DT-MRI), we demonstrate that microstructural WMabnormalities occur from an early age in YAC128 mice. Similarly, electron microscopy analysis of myelinated fibres of the corpus callosum indicated that myelin sheaths are thinner in YAC128 mice as early as 1.5 months of age, well before any neuronal loss can be detected. Transcript levels of myelin-related genes in striatal and cortical tissues were significantly lower in YAC128 mice from 2 weeks of age, and these findings were replicated in differentiated primary oligodendrocytes from YAC128 mice, suggesting a possible mechanistic explanation for the observed structural deficits. Concordant with these observations, we demonstrate reduced expression of myelin-related genes at 3 months of age and WMmicrostructural abnormalities using DT-MRI at 12 months of age in the BACHD rats. These findings indicate thatWM deficits in HD are an early phenotype associated with cell-intrinsic effects of mutant huntingtin on myelin-related transcripts in oligodendrocytes, and raise the possibility thatWMabnormalities may be an early contributing factor to the pathogenesis of HD

Therapeutic modulation of the bile acid pool by Cyp8b1 knockdown protects against nonalcoholic fatty liver disease in mice

Bile acids (BAs) are surfactant molecules that regulate the intestinal absorption of lipids. Thus, the modulation of BAs represents a potential therapy for nonalcoholic fatty liver disease (NAFLD), which is characterized by hepatic accumulation of fat and is a major cause of liver disease worldwide. Cyp8b1 is a critical modulator of the hydrophobicity index of the BA pool. As a therapeutic proof of concept, we aimed to determine the impact of Cyp8b1 inhibition in vivo on BA pool composition and as protection against NAFLD. Inhibition of Cyp8b1 expression in mice led to a remodeling of the BA pool, which altered its signaling properties and decreased intestinal fat absorption. In a model of cholesterol-induced NAFLD, Cyp8b1 knockdown significantly decreased steatosis and hepatic lipid content, which has been associated with an increase in fecal lipid and BA excretion. Moreover, inhibition of Cyp8b1 not only decreased hepatic lipid accumulation, but also resulted in the clearance of previously accumulated hepatic cholesterol, which led to a regression in hepatic steatosis. Taken together, our data demonstrate that Cyp8b1 inhibition is a viable therapeutic target of crucial interest for metabolic diseases, such as NAFLD.-Chevre, R., Trigueros-Motos, L., Castaño, D., Chua, T., Corlianò, M., Patankar, J. V., Sng, L., Sim, L., Juin, T. L., Carissimo, G., Ng, L. F. P., Yi, C. N. J., Eliathamby, C. C., Groen, A. K., Hayden, M. R., Singaraja, R. R. Therapeutic modulation of the bile acid pool by Cyp8b1 knockdown protects against nonalcoholic fatty liver disease in mic

Haploinsufficiency of CYP8B1 associates with increased insulin sensitivity in humans

BACKGROUND. Cytochrome P450 family 8 subfamily B member 1 (CYP8B1) generates 12α-hydroxylated bile acids (BAs) that are associated with insulin resistance in humans. METHODS. To determine whether reduced CYP8B1 activity improves insulin sensitivity, we sequenced CYP8B1 in individuals without diabetes and identified carriers of complete loss-of-function (CLOF) mutations utilizing functional assays. RESULTS. Mutation carriers had lower plasma 12α-hydroxylated/non-12α-hydroxylated BA and cholic acid (CA)/chenodeoxycholic acid (CDCA) ratios compared with age-, sex-, and BMI-matched controls. During insulin clamps, hepatic glucose production was suppressed to a similar magnitude by insulin, but glucose infusion rates to maintain euglycemia were higher in mutation carriers, indicating increased peripheral insulin sensitivity. Consistently, a polymorphic CLOF CYP8B1 mutation associated with lower fasting insulin in the AMP-T2D-GENES study. Exposure of primary human muscle cells to mutation-carrier CA/CDCA ratios demonstrated increased FOXO1 activity, and upregulation of both insulin signaling and glucose uptake, which were mediated by increased CDCA. Inhibition of FOXO1 attenuated the CDCA-mediated increase in muscle insulin signaling and glucose uptake. We found that reduced CYP8B1 activity associates with increased insulin sensitivity in humans. CONCLUSION. Our findings suggest that increased circulatory CDCA due to reduced CYP8B1 activity increases skeletal muscle insulin sensitivity, contributing to increased whole-body insulin sensitization. FUNDING. Biomedical Research Council/National Medical Research Council of Singapore