Histone Deacetylases as Epigenetic Targets for Treating Parkinson’s Disease

Li, Yan; Gu, Zhicheng; Lin, Shuxian; Chen, Lei; Dzreyan, Valentina; Eid, Moez; Demyanenko, Svetlana; He, Bin

doi:10.3390/brainsci12050672

Cited by 17 publications

(6 citation statements)

References 145 publications

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“…Butyrate has also been used to differentiate cancer cell-line cultures to a "dopaminergic" phenotype (1 mM dosage) via inhibition of histone deacetylase (HDAC) 35 . Histone acetylation is an epigenetic modification linked with aging and neurodegenerative disease [36][37][38] . Toker et al reported elevated histone acetylation in idiopathic PD patients compared to healthy control patients 36 .…”

Section: Resultsmentioning

confidence: 99%

Aggregation of alpha-synuclein in enteric neurons does not impact function in vitro

Bindas

Roth

Brady

et al. 2022

Sci Rep

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Recent evidence implicates a gut-first pathogenesis in the enteric nervous system (ENS) within a portion of PD patients, yet in vitro investigations have primarily focused on the central nervous system. Here, the preformed fibril (PFF) PD model is applied with co-administered groups of butyrate and lipopolysaccharide to model the effects of the local gut microbiome. Significant PFF uptake and retention occur in isolated rat enteric neurons compared to untreated controls resulting in increasing immunostained aggregate conformation-specific, alpha-synuclein (a-Syn) average intensity between 6 µg PFF and untreated controls. Cortical neurons significantly retain PFFs with an increase in aggregated a-Syn average intensity within all dosages. Differences in growth cone morphology but not dynamics in PFF-treated ENS cultures occur. Electrophysiological recordings via a microelectrode array (MEA) indicate no overall difference in spontaneous spike rate. However, only untreated controls respond to PD-relevant dopamine stimulus, while 1 µg PFF and control populations respond to stimulus with ENS-abundant acetylcholine. Finally, no differences in substance P levels—correlated with PD and neurodegeneration—are observed. Overall, these findings suggest the ENS retains PFF dosage absent acute loss in function, however, does experience changes in growth cone morphology and dopamine-stimulated activity.

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Section: Resultsmentioning

confidence: 99%

Aggregation of alpha-synuclein in enteric neurons does not impact function in vitro

Bindas

Roth

Brady

et al. 2022

Sci Rep

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“…Additional evidence points to butyrate potentially providing protection against neurodegeneration via the ability to inhibit histone deacetylates (HDAC) [88][89][90][91] . HDAC inhibitors have been shown to have neuroprotective effects in PD, and other neurodegenerative diseases, by increasing protein acetylation and promoting downstream gene expression and modulation of immune responses [92][93][94] . In models of colitis, HDAC inhibitors have been shown to reduce colitis severity and decrease colonic TNF 95 .…”

Section: Discussionmentioning

confidence: 99%

A comparative analysis of Parkinson’s disease and inflammatory bowel disease gut microbiomes highlights shared depletions in key butyrate-producing bacteria

Krueger,

Boles,

Simon

et al. 2024

Preprint

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Epidemiological studies reveal that a diagnosis of inflammatory bowel disease (IBD) is associated with an increased risk of developing Parkinson's disease (PD). The presence of gut dysbiosis has been documented in both PD and IBD patients, however it is currently unknown how alterations in the gut microbiome may contribute to the epidemiological link between both diseases. To identify shared and distinct features of the PD and IBD microbiome, we performed the first joint analysis of 54 PD, 26 IBD, and 16 healthy control gut metagenomes recruited from clinics at the University of Florida, and directly compared the gut microbiomes from PD and IBD persons. Larger, publicly available PD and IBD metagenomic datasets were also analyzed to validate and extend our findings. Depletions in short-chain fatty acid (SCFA) producing bacteria, including Roseburia intestinalis, Faecalibacterium prausnitzii, Anaerostipes hadrus, and Eubacterium rectale, as well as depletions in SCFA synthesis pathways, were demonstrated across PD and IBD datasets. We posit that direct comparison of PD and IBD gut microbiomes will be important in identifying features within the IBD gut which may be associated with PD. The data revealed a consistent depletion in SCFA-producing bacteria across both PD and IBD, suggesting that loss of these microbes may influence the pathophysiology of both disease states.

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“…Exposure to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) destroys dopaminergic neurons and causes PD-like symptoms, but it also increases the levels of histone H3 acetylation, which are reduced by treatment with levodopa [ 54 ]. High levels of histone H2A, H3, and H4 acetylation are present in dopaminergic neurons in post-mortem PD patients [ 55 ]. Indeed, treatment with HDAC inhibitors reduces α-synuclein neurotoxicity in neuroblastoma cells and in dopaminergic neurons in the α-synuclein transgenic Drosophila model of PD [ 52 , 56 , 57 ].…”

Section: Epigenetics In Neurodegenerative Disordersmentioning

confidence: 99%

Natural Bioactive Products as Epigenetic Modulators for Treating Neurodegenerative Disorders

et al. 2023

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Neurodegenerative disorders (NDDs) are major health issues in Western countries. Despite significant efforts, no effective therapeutics for NDDs exist. Several drugs that target epigenetic mechanisms (epidrugs) have been recently developed for the treatment of NDDs, and several of these are currently being tested in clinical trials. Furthermore, various bioproducts have shown important biological effects for the potential prevention and treatment of these disorders. Here, we review the use of natural products as epidrugs to treat NDDs in order to explore the epigenetic effects and benefits of functional foods and natural bioproducts on neurodegeneration.

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Histone Deacetylases as Epigenetic Targets for Treating Parkinson’s Disease

Cited by 17 publications

References 145 publications

Aggregation of alpha-synuclein in enteric neurons does not impact function in vitro

Aggregation of alpha-synuclein in enteric neurons does not impact function in vitro

A comparative analysis of Parkinson’s disease and inflammatory bowel disease gut microbiomes highlights shared depletions in key butyrate-producing bacteria

Natural Bioactive Products as Epigenetic Modulators for Treating Neurodegenerative Disorders

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