Epigenetic Landscape of Parkinson's Disease: Emerging Role in Disease Mechanisms and Therapeutic Modalities

Kaidery, Navneet Ammal; Tarannum, Shaista; Thomas, Bobby

doi:10.1007/s13311-013-0211-8

Cited by 76 publications

(62 citation statements)

References 83 publications

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“…Epigenetic changes in PD-related genes also contribute to PD pathogenesis and epigenetic drugs might constitute a potential therapeutic option in the future [26,34,35,72,73,74,75,76,77]. …”

Section: Pathogenic Mechanismsmentioning

confidence: 99%

Parkinson’s Disease: From Pathogenesis to Pharmacogenomics

Cacabelos

2017

IJMS

434

300

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Parkinson’s disease (PD) is the second most important age-related neurodegenerative disorder in developed societies, after Alzheimer’s disease, with a prevalence ranging from 41 per 100,000 in the fourth decade of life to over 1900 per 100,000 in people over 80 years of age. As a movement disorder, the PD phenotype is characterized by rigidity, resting tremor, and bradykinesia. Parkinson’s disease -related neurodegeneration is likely to occur several decades before the onset of the motor symptoms. Potential risk factors include environmental toxins, drugs, pesticides, brain microtrauma, focal cerebrovascular damage, and genomic defects. Parkinson’s disease neuropathology is characterized by a selective loss of dopaminergic neurons in the substantia nigra pars compacta, with widespread involvement of other central nervous system (CNS) structures and peripheral tissues. Pathogenic mechanisms associated with genomic, epigenetic and environmental factors lead to conformational changes and deposits of key proteins due to abnormalities in the ubiquitin–proteasome system together with dysregulation of mitochondrial function and oxidative stress. Conventional pharmacological treatments for PD are dopamine precursors (levodopa, l-DOPA, l-3,4 dihidroxifenilalanina), and other symptomatic treatments including dopamine agonists (amantadine, apomorphine, bromocriptine, cabergoline, lisuride, pergolide, pramipexole, ropinirole, rotigotine), monoamine oxidase (MAO) inhibitors (selegiline, rasagiline), and catechol-O-methyltransferase (COMT) inhibitors (entacapone, tolcapone). The chronic administration of antiparkinsonian drugs currently induces the “wearing-off phenomenon”, with additional psychomotor and autonomic complications. In order to minimize these clinical complications, novel compounds have been developed. Novel drugs and bioproducts for the treatment of PD should address dopaminergic neuroprotection to reduce premature neurodegeneration in addition to enhancing dopaminergic neurotransmission. Since biochemical changes and therapeutic outcomes are highly dependent upon the genomic profiles of PD patients, personalized treatments should rely on pharmacogenetic procedures to optimize therapeutics.

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“…Epigenetic changes in PD-related genes also contribute to PD pathogenesis and epigenetic drugs might constitute a potential therapeutic option in the future [26,34,35,72,73,74,75,76,77]. …”

Section: Pathogenic Mechanismsmentioning

confidence: 99%

Parkinson’s Disease: From Pathogenesis to Pharmacogenomics

Cacabelos

2017

IJMS

434

300

View full text Add to dashboard Cite

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“…DNMT3A and DNMT3B known as the de novo DNA methyltransferases are able to transfer methyl group to unmethylated CpGs in DNA (Li and Zhang 2014). Aberrant DNA methylation patterns in the genome are associated with various pathological processes and age-related diseases, including cancer, neurodegenerative diseases such as Alzheimer's and Parkinson's diseases, osteoarthritis, type 2 diabetes, and renal disease (Ammal Kaidery et al 2013;De Jager et al 2014;Alvarez et al 2014;Hoile et al 2014). In ALS patients, increased expression of DNMT1 and DNMT3A has been observed in motor cortex tissues and spinal cord motor neurons (Chestnut et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Functional Restoration of Amyotrophic Lateral Sclerosis Patient-Derived Mesenchymal Stromal Cells Through Inhibition of DNA Methyltransferase

Kim

Cho

2015

Cell Mol Neurobiol

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Alteration of DNA methylation is highly associated with aging and neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS). Remedying these aberrant methylation patterns may serve to improve these diseases. Previously, we reported that human bone marrow mesenchymal stromal cells isolated from ALS patients (ALS-MSCs) have functionally decreased stem cell potency, and excessively express DNA methyltransferases (DNMTs). In this study, we examined the correlation between excessive DNMT expression and functional decline in ALS-MSCs. The DNMT inhibitor RG108 was used for this. RG108-treated ALS-MSCs exhibit increased expression of the anti-senescence genes TERT, VEGF, and ANG, and decreased expression of the senescence-related genes ATM and p21. The activity of SA-β-galactosidase and the expression of senescence proteins p53 and p16 were reduced in RG108-treated ALS-MSCs. The abilities of cell migration and protection against oxidative damage were improved in the treated ALS-MSCs. In neuronal differentiation experiments, the treated MSCs more effectively differentiated into neuron-like cells. These results suggest that ALS-MSC function can be restored by inhibiting excessively expressed DNMTs, an approach that may ultimately provide better efficacy in stem cell therapy.

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“…Epigenetics refers to alterations in gene expression or function without changes in DNA sequence [84], which mainly includes DNA methylation, postmodifications of histone, and non-coding RNAs. This process can be influenced by lifestyle, environmental factors and modifying genes, resulting in expression but also play a vital role in development, regeneration, and in human diseases such as NDD [85].…”

Section: Epigenetics Nutrigenomicsmentioning

confidence: 99%

Current Understanding on the Beneficial Role of Nutrition in Parkinson’s Disease –An Overview

Muralidhara¹,

Sv²,

SC³

2017

J Aging Sci

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Various nutritional components belonging to different classes of natural dietary origin display modulatory (protective) properties against age-related neurodegenerative disorders (NDD) such as Parkinson's disease (PD) and Alzheimer's disease. These compounds termed as nutraceuticals which have been shown to act at various biochemical and metabolic levels and exhibit different degree of neuroprotective properties. Present review aims to summarize the current status on the modulatory impact of some of the major nutritional compounds on the pathophysiology of PD, the second most common NDD in humans. Primarily, we have examined the data demonstrated in animal models and postulated through epidemiological studies on the compounds/molecules/life style factors which reduce the risk associated with PD and probable mechanism/s through which they elicit neuroprotection. Further we also included some of the conflicting information about the compounds which may enhance the risk associated with PD. Additionally, emphasis is also given about the new approaches to understand the impact of nutrition on the epigenome in relation to the development of NDD with a short note on emerging ideas relating to nutritional genomics.

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Epigenetic Landscape of Parkinson's Disease: Emerging Role in Disease Mechanisms and Therapeutic Modalities

Cited by 76 publications

References 83 publications

Parkinson’s Disease: From Pathogenesis to Pharmacogenomics

Parkinson’s Disease: From Pathogenesis to Pharmacogenomics

Functional Restoration of Amyotrophic Lateral Sclerosis Patient-Derived Mesenchymal Stromal Cells Through Inhibition of DNA Methyltransferase

Current Understanding on the Beneficial Role of Nutrition in Parkinson’s Disease –An Overview

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