Epigenetics of Alzheimer's Disease and Frontotemporal Dementia

Veerappan, Chendhore S.; Sleiman, Sama F.; Coppola, Giovanni

doi:10.1007/s13311-013-0219-0

Cited by 30 publications

(24 citation statements)

References 159 publications

(169 reference statements)

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“…While research identifying epigenetic pathogenic mechanisms is still in its infancy for ALS and FTD, lessons learned from other diseases, especially cancer, have the potential to fast-track the development of epigenetic targeting strategies from bench to bedside to treat ALS and FTD. Drugs already approved to target epigenetic mechanisms may turn out to be efficacious and restore altered cellular pathways in ALS and FTD; already FDA approved to treat cancer, Dnmt and HDAC inhibitors [76,53] may be able to reverse aberrant epigenetic changes in the central nervous system [184]. Thus, the emerging field of epigenetics provides new hope for patients with lethal ALS and FTD, and exciting studies exploring new territories should be expected in the near future.…”

Section: Discussionmentioning

confidence: 99%

“…In fact, the mechanism of de novo gene methylation was first demonstrated in plants in 1994, and for the first time embraced the possibility of artificially modulating gene expression through epigenetic modulation [186]. Strategies to therapeutically reverse pathogenic changes in DNA methylation have been intensely studied since then to treat many diseases, including cancer and neurodegeneration [76,184]. Interestingly, to combat the potential toxicity associated with C9orf72 haploinsufficiency, small molecules targeting bromodomain proteins, proteins that recognize acetylated lysine residues on chromatin, have been shown to specifically enhance C9orf72 RNA expression without affecting the epigenetic regulation of this gene [193].…”

Section: The Role Of Epigenetic Regulation In Als and Ftdmentioning

confidence: 99%

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ALS and FTD: an epigenetic perspective

2016

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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two fatal neurodegenerative diseases seen in comorbidity in up to 50% of cases. Despite tremendous efforts over the last two decades, no biomarkers or effective therapeutics have been identified to prevent, decelerate or stop neuronal death in patients. While the identification of multiple mutations in more than two dozen genes elucidated the involvement of several mechanisms in the pathogenesis of both diseases, identifying the hexanuceotide repeat expansion in C9orf72, the most common genetic abnormality in ALS and FTD, opened the door to the discovery of several novel pathogenic biological routes, including chromatin remodeling and transcriptome alteration. Epigenetic processes regulate DNA replication and repair, RNA transcription, and chromatin conformation, which in turn further dictate transcriptional regulation and protein translation. Transcriptional and post-transcriptional epigenetic regulation is mediated by enzymes and chromatin-modifying complexes that control DNA methylation, histone modifications, and RNA editing. While alteration of DNA methylation and histone modification have recently been reported in ALS and FTD, assessment of epigenetic involvement in both diseases is still at an early stage, and the involvement of multiple epigenetic players still needs to be evaluated. As the epigenome serves as a way to alter genetic information not only during aging, but also following environmental signals, epigenetic mechanisms might play a central role in initiating ALS and FTD, especially for sporadic cases. Here, we provide a review of what is currently known about altered epigenetic processes in both ALS and FTD, and discuss potential therapeutic strategies targeting epigenetic mechanisms. As approximately 85% of ALS and FTD cases are still genetically unexplained, epigenetic therapeutics explored for other diseases might represent a profitable direction for the field.

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Section: Discussionmentioning

confidence: 99%

Section: The Role Of Epigenetic Regulation In Als and Ftdmentioning

confidence: 99%

ALS and FTD: an epigenetic perspective

2016

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“…Disorders in the other allele may result in disorders such as Prader-Willi and Angelman syndrome, and efforts are under way to utilize therapies to reprogram to a normal developmental program (26). DNA methylation and noncoding RNA interference may also play a role in other disease states such as Alzheimer’s disease and frontotemporal dementia (27). …”

Section: Dna Methylation In Normal and Disease Epigenomesmentioning

confidence: 99%

Epigenetic Therapeutics: A New Weapon in the War Against Cancer

Ahuja

Sharma²,

Baylin³

2016

Annu. Rev. Med.

318

228

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The past 15 years have seen an explosion of discoveries related to the cellular regulation of phenotypes through epigenetic mechanisms. This regulation provides a software that packages DNA, without changing the primary base sequence, to establish heritable patterns of gene expression. In cancer, many aspects of the epigenome, controlled by DNA methylation, chromatin, and nucleosome positioning, are altered as one means by which tumor cells maintain abnormal states of self-renewal at the expense of normal maturation. Epigenetic and genetic abnormalities thus collaborate in cancer initiation and progression, as exemplified by frequent mutations in genes encoding proteins that control the epigenome. There is growing emphasis on using epigenetic therapies to reprogram neoplastic cells toward a normal state. Many agents targeting epigenetic regulation are under development and entering clinical trials. This review highlights the promise that epigenetic therapy, often in combination with other therapies, will become a potent tool for cancer management over the next decade.

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“…DNA methylation, histone modifications and chromatin remodeling and non-coding RNA dysregulation may contribute to AD pathology, although evidence is still very limited [9,15,16,[54][55][56]. Pharmaceuticals, pesticides, air pollutants, industrial chemicals, heavy metals, hormones, nutrition, and behavior can change gene expression through a broad array of gene regulatory mechanisms.…”

Section: Epigenomics Of Alzheimer's Diseasementioning

confidence: 99%

Epigenetics of Brain Disorders: The Paradigm of Alzheimer ’s Disease

Cacabelos¹

2016

J Alzheimers Dis Parkinsonism

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Over 80% of brain disorders are associated with multiple genomic defects in conjunction with environmental factors and epigenetic phenomena. Classical epigenetic mechanisms, including DNA methylation, histone modifications, and microRNAs (miRNAs) regulation, are among the major regulatory elements that control metabolic pathways at the molecular level, with epigenetic modifications controlling gene expression transcriptionally and miRNAs suppressing gene expression post-transcriptionally. Epigenetic modifications are related to disease development, environmental exposure, drug treatment and aging. Epigenetic changes are reversible and can be potentially targeted by pharmacological intervention. Both hypermethylation and hypomethylation of DNA, chomatin changes and miRNA dysregulation are common in age-related disorders and in many neuropsychiatric, neurodevelopmental and neurodegenerative disorders. Major epigenetic mechanisms may contribute to Alzheimer's disease (AD) pathology. Several pathogenic genes and many other AD-related susceptibility genes contain methylated CpG sites. AD brains exhibit a genome-wide decrease in DNA methylation. Pathogenic histone modifications are present in AD. Alterations in epigentically regulated miRNAs may contribute to the abnormal expression of pathogenic genes in AD. Epigenetic drugs can reverse epigenetic changes in gene expression and might open future avenues in AD therapeutics. Individual differences in drug response are associated with genetic and epigenetic variability and disease determinants. Pharmacoepigenomics deals with the influence that epigenetic alterations may exert on genes involved in the pharmacogenomic network (pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes) responsible for the pharmacokinetics and pharmacodynamics of drugs (efficacy and safety), as well as the effects that drugs may have on the epigenetic machinery. family), AID/APOBEC family, and the VER glycosylase family [9]. Histone acetylation is achieved by histone acetyltransferase (HAT); and histone deacetylation is produced by histone deacetylases (HDACs) (class I: HDAC1, 2, 3, and 8; class IIa: HDAC4, 5,7, and 9; class IIb: HDAC6 and 10; class III: SIRT1, 2, 6, 7; class IV: HDAC11) [9].Long non-coding (lnc) RNAs are non-protein-coding RNAs, distinct from housekeeping RNAs (tRNAs, rRNAs, and snRNAs) and independent from small RNAs with specific molecular processing machinery. Over 95% of the eukaryotic genome is transcribed into non-coding RNAs and less than 5% is translated. LncRNA-mediated epigenetic regulation depends on lcnRNA interactions with proteins or genomic DNA via RNA secondary structures [10].Epigenomic modifications are involved in a great variety of physiological and pathological conditions; of major importance are those related with major problems of health such as cardiovascular disorders, obesity, cancer, inflammatory processes, and brain disorders [11,12]. A good paradigm on the influence of epigenetic factors on human pathology is the oncogenic ...

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Epigenetics of Alzheimer's Disease and Frontotemporal Dementia

Abstract: This article will review the recent advances in the understanding of the role of epigenetic modifications and the promise of future epigenetic therapy in neurodegenerative dementias, including Alzheimer's disease and frontotemporal dementia.

Cited by 30 publications

References 159 publications

ALS and FTD: an epigenetic perspective

ALS and FTD: an epigenetic perspective

Epigenetic Therapeutics: A New Weapon in the War Against Cancer

Epigenetics of Brain Disorders: The Paradigm of Alzheimer ’s Disease

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