DNA methylation in Huntington’s disease: Implications for transgenerational effects

Thomas, Elizabeth A.

doi:10.1016/j.neulet.2015.10.060

Cited by 31 publications

(18 citation statements)

References 73 publications

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“…Immunological status, evidenced by CD4 count was also seen to be associated with VL, with PLHA with CD4 less than 500 showing more virological failure than those with CD4 count more than 500. This result is in concordance with multiple studies reporting similar findings [10,19,36]. Among those with baseline VL>1000c/ml, follow-up viral suppression was significantly associated with EAC.…”

Section: Discussionsupporting

confidence: 93%

Routine viral load monitoring and enhanced adherence counselling at a public ART centre in Mumbai, India

Laxmeshwar¹,

Acharya

Das³

et al. 2020

PLoS ONE

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Background Routine viral-load (VL) measurements along with enhanced adherence counselling (EAC) are recommended to achieve virological suppression among people living with HIV/AIDS (PLHA) on anti-retroviral therapy (ART). The Mumbai Districts AIDS Control Society along with Mé decins Sans Frontières has provided routine VL measurements and EAC to PLHA on ART at King Edward Memorial (KEM) hospital, Mumbai since October-2016. This study aims to describe the initial VL results and impact of EAC on viral suppression and factors associated with initial viral non-suppression among patients with an initial detectable VL, in a cohort of patients tested between October-2016 and September-2018. Methods This is a descriptive study of PLHA on ART who received VL testing and EAC during October-2016 to September-2018. Log-binomial regression was used to identify factors associated with a high VL. Results Among 3849 PLHA who underwent VL testing, 1603(42%) were female and median age was 42 years (IQR:35-48). Majority were referred for routine testing (3432(89%)) and clinical/immunological failure (233(6%)). Overall, 3402(88%) PLHA had suppressed VL at initial testing. Among 3432 tested for routine monitoring, 3141(92%) had VL suppressed. Of 291 with VL>1000c/ml, 253(87%) received EAC and after repeat VL, 70(28%) had VL<1000c/ ml. Among 233 referred for clinical/immunological failure, 122(52%) had VL>1000c/ml and 109 have been switched to second-line ART. CD4 count<500 (aOR-5.0[95%CI 3.8-6.5]), on ART for<5 years (aOR-1.5[1.1-2.0]) and age<15 years (aOR-5.2[3.0-8.9]) were associated with an initial VL>1000c/ml. Factors

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Section: Discussionsupporting

confidence: 93%

Routine viral load monitoring and enhanced adherence counselling at a public ART centre in Mumbai, India

Laxmeshwar¹,

Acharya

Das³

et al. 2020

PLoS ONE

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“…Several of the disorders discussed above may be susceptible to epigenetic influences. The brains of patients with Huntington's disease exhibit evidence of alterations in methylation status (207,208) or acetylation status (209) and inhibition of a histone deacetylase may prevent the development of cognitive deficits as well as huntingtin expansion (210). Such changes may contribute significantly to the course of the disorder and its heritability, especially since DNA methylation has been shown to produce extension of the mutant CAG repeat sequence (211).…”

Section: Epigenetics Of Idomentioning

confidence: 99%

IDO and Kynurenine Metabolites in Peripheral and CNS Disorders

et al. 2020

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The importance of the kynurenine pathway in normal immune system function has led to an appreciation of its possible contribution to autoimmune disorders such as rheumatoid arthritis. Indoleamine-2,3-dioxygenase (IDO) activity exerts a protective function, limiting the severity of experimental arthritis, whereas deletion or inhibition exacerbates the symptoms. Other chronic disorder with an inflammatory component, such as atherosclerosis, are also suppressed by IDO activity. It is suggested that this overall anti-inflammatory activity is mediated by a change in the relative production or activity of Th17 and regulatory T cell populations. Kynurenines may play an anti-inflammatory role also in CNS disorders such as Huntington's disease, Alzheimer's disease and multiple sclerosis, in which signs of inflammation and neurodegeneration are involved. The possibility is discussed that in Huntington's disease kynurenines interact with other anti-inflammatory molecules such as Human Lymphocyte Antigen-G which may be relevant in other disorders. Kynurenine involvement may account for the protection afforded to animals with cerebral malaria and trypanosomiasis when they are treated with an inhibitor of kynurenine-3-monoxygenase (KMO). There is some evidence that changes in IL-10 may contribute to this protection and the relationship between kynurenines and IL-10 in arthritis and other inflammatory conditions should be explored. In addition, metabolites of kynurenine downstream of KMO, such as anthranilic acid and 3-hydroxy-anthranilic acid can influence inflammation, and the ratio of these compounds is a valuable biomarker of inflammatory status although the underlying molecular mechanisms of the changes require clarification. Hence it is essential that more effort be expended to identify their sites of action as potential targets for drug development. Finally, we discuss increasing awareness of the epigenetic regulation of IDO, for example by DNA methylation, a phenomenon which may explain differences between individuals in their susceptibility to arthritis and other inflammatory disorders.

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“…The transcriptional regulation of ATP13A2 and ATP7B with MnCl2 and DMOG suggests to us that changes in the expression of related genes are associated with MnCl2-induced neurodegenerative disorders and their antagonism by DMOG. Recently, emerging results have shown that DNA methylation plays an important role in various major neurodegenerative diseases, including Alzheimer’s disease (AD) 28 , Parkinson’s disease (PD) 29 , Huntington’s disease (HD) 30 , and amyotrophic lateral sclerosis (ALS) 31 . Meanwhile, methylation changes in a series of important functional genes have been found to be correlated with neurodegeneration in multiple diseases.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide analysis of DNA methylation during antagonism of DMOG to MnCl2-induced cytotoxicity in the mouse substantia nigra

Yang

Wei

Wang

et al. 2016

Sci Rep

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Exposure to excessive manganese (Mn) causes manganism, a progressive neurodegenerative disorder similar to idiopathic Parkinson’s disease (IPD). The detailed mechanisms of Mn neurotoxicity in nerve cells, especially in dopaminergic neurons are not yet fully understood. Meanwhile, it is unknown whether there exists a potential antagonist or effective drug for treating neuron damage in manganism. In the present study, we report the discovery of an HIF prolyl-hydroxylase inhibitor, DMOG [N-(2-Methoxy-2-oxoacetyl) glycine methyl ester], that can partially inhibit manganese toxicity not only in the neuroblastoma cell line SH-SY5Y in vitro but also in a mouse model in vivo. A genome-wide methylation DNA analysis was performed using microarray hybridization. Intriguingly, DNA methylation in the promoter region of 226 genes was found to be regulated by MnCl2, while the methylation effects of MnCl2 could be restored with combinatorial DMOG treatment. Furthermore, we found that genes with converted promoter methylation during DMOG antagonism were associated across several categories of molecular function, including mitochondria integrity maintain, cell cycle and DNA damage response, and ion transportation. Collectively, our results serve as the basis of a mechanism analysis of neuron damage in manganism and may supply possible gene targets for clinical therapy.

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DNA methylation in Huntington’s disease: Implications for transgenerational effects

Cited by 31 publications

References 73 publications

Routine viral load monitoring and enhanced adherence counselling at a public ART centre in Mumbai, India

Routine viral load monitoring and enhanced adherence counselling at a public ART centre in Mumbai, India

IDO and Kynurenine Metabolites in Peripheral and CNS Disorders

Genome-wide analysis of DNA methylation during antagonism of DMOG to MnCl2-induced cytotoxicity in the mouse substantia nigra

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