Hypermethylation of the Gene Coding for PGC-1α in Peripheral Blood Leukocytes of Patients With Parkinson’s Disease

Yang, Xiaodong; Xu, S. B.; Qian, Yiwei; He, Xiaoqin; Chen, Shengdi; Xiao, Qin

doi:10.3389/fnins.2020.00097

Cited by 19 publications

(15 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A connection between PGC-1α methylation and mtDNA copy number is established, and a negative correlation is reported between PGC-1α promoter methylation and both PGC-1α transcription and mtDNA copy number in neurological (53) and metabolic disorders (31,33,70). Consistent with this, we report a negative correlation between PGC-1α promoter hypermethylation and both mtDNA copy number and deletions in our control group.…”

Section: Discussionmentioning

confidence: 95%

“…Our data show genes that regulate mitochondrial biogenesis, fission and fusion are DM in our cohort. While we were unable to measure gene expression because of the low integrity of RNA extracted from the tissue source (buccal swabs) used in our study, previous studies have shown that differential methylation alters the expression of these genes (20,42,43,53). We investigated whether mitochondrial DNA copy number, a marker of mitochondrial function (46), was altered in our cohort.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

DNA methylation of PGC-1α is associated with elevated mtDNA copy number and altered urinary metabolites in Autism Spectrum Disorder

Bam

Buchanan

Mahony

et al. 2021

Preprint

View full text Add to dashboard Cite

BackgroundAutism Spectrum Disorder (ASD) is a complex disorder that is underpinned by numerous dysregulated biological pathways, including canonical mitochondrial pathways. Epigenetic mechanisms contribute to this dysregulation and DNA methylation is an important factor in the aetiology of ASD. We examined the relationship between DNA methylation of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), an essential transcriptional regulator of mitochondrial homeostasis, and mitochondrial dysfunction in an ASD cohort of South African children.ResultsUsing targeted Next Generation bisulfite sequencing, we found 12 highly variable CpG sites in PGC-1α that were significantly differentially methylated (p<0.05) between ASD (n = 55) and controls (n = 44). In ASD, eight CpG sites were hypermethylated in the PGC-1α promotor with a putative binding site for CAMP response binding element 1 (CREB1) spanning one of these CpG sites (p = 1 × 10−6). Mitochondrial DNA (mtDNA) copy number, a marker of mitochondrial function, was elevated (p = 0.002) in ASD compared to controls and correlated significantly with DNA methylation at the PGC-1α promoter. There was a positive correlation between methylation at PGC-1α at CpG#1 and mtDNA copy number (Spearman’s r = 0.2, n = 49, p = 0.04) in ASD, but a negative correlation between methylation at PGC-1α at CpG#4 promoter and mtDNA copy number in controls (Spearman’s r = −0.4, n = 42, p = 0.045). While there was no relationship between mtDNA deletions and PGC-1α methylation in ASD, mtDNA deletions correlated negatively with methylation at PGC-1α at CpG#4 (Spearman’s r = −0.4, n = 42, p = 0.032) in controls. Furthermore, levels of urinary organic acids associated with mitochondrial dysfunction correlated significantly (p<0.05) with DNA methylation at PGC-1α CpG#1 and mtDNA copy number in ASD (n= 20) and controls (n= 13) with many of these metabolites involved in altered redox homeostasis and neuroendocrinology.ConclusionsThese data show an association between PGC-1α promoter methylation, elevated mtDNA copy number and metabolomic evidence of mitochondrial dysfunction in ASD. This highlights an unexplored link between DNA methylation and mitochondrial dysfunction in ASD.

show abstract

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

DNA methylation of PGC-1α is associated with elevated mtDNA copy number and altered urinary metabolites in Autism Spectrum Disorder

Bam

Buchanan

Mahony

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…For instance, regarding the genes with aberrant methylation, PPARGC1A (the gene encoding PGC-1α) and HLA-DRB5 (involved in neuroinflammation and immune system) could be suitable PD biomarker candidates. Both have been reported as hypermethylated in independent studies and in different tissues: PPARGC1A in the SN and peripheral blood [ 172 , 173 ], and HLA-DRB5 in peripheral blood and frontal cortex [ 151 , 154 ] ( Figure 2 ). HLA-DRB5 is also hypermethylated in AD [ 174 ]; additional studies should determine the sensitivity and specificity of this potential biomarker for PD.…”

Section: Epigenetic Pattern As Lbd Biomarkermentioning

confidence: 99%

Epigenetics in Lewy Body Diseases: Impact on Gene Expression, Utility as a Biomarker, and Possibilities for Therapy

Urbizu

Beyer

2020

IJMS

View full text Add to dashboard Cite

Lewy body disorders (LBD) include Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). They are synucleinopathies with a heterogeneous clinical manifestation. As a cause of neuropathological overlap with other neurodegenerative diseases, the establishment of a correct clinical diagnosis is still challenging, and clinical management may be difficult. The combination of genetic variation and epigenetic changes comprising gene expression-modulating DNA methylation and histone alterations modifies the phenotype, disease course, and susceptibility to disease. In this review, we summarize the results achieved in the deciphering of the LBD epigenome. To provide an appropriate context, first LBD genetics is briefly outlined. Afterwards, a detailed review of epigenetic modifications identified for LBD in human cells, postmortem, and peripheral tissues is provided. We also focus on the difficulty of identifying epigenome-related biomarker candidates and discuss the results obtained so far. Additionally, epigenetic changes as therapeutic targets, as well as different epigenome-based treatments, are revised. The number of studies focusing on PD is relatively limited and practically inexistent for DLB. There is a lack of replication studies, and some results are even contradictory, probably due to differences in sample collection and analytical techniques. In summary, we show the current achievements and directions for future research.

show abstract

“…The selective knockout of different PGC-1α isoforms in mice may lead to a decrease of dopamine content in the striatum and to an associated loss of DA neurons [ 148 ]. Accordingly, in human PD tissues, the levels of PGC-1α and of mitochondrial markers are reduced compared to control patients and are negatively correlated with the severity of the disease [ 148 , 153 , 154 , 155 , 156 , 157 ]. Conversely, primary fibroblasts from PD patients display upregulation of PGC-1α, even if its target genes involved in mitochondrial biogenesis and fatty acid β-oxidation processes are unchanged or downregulated and mitochondria display significant morphometric changes [ 158 , 159 ].…”

Section: Pgc-1s In Parkinson’s Diseasementioning

confidence: 99%

“…The low expression of PGC-1α observed in the PD brain is probably due to the high level of gene methylation that has been found in PD patients [ 155 ]. Dense DNA methylation is usually associated with gene repression, and the PGC-1α promoter is proximal to a non-canonical cytosine methylation site that is epigenetically modified in the brain of sporadic PD patients [ 153 ].…”

Section: Pgc-1s In Parkinson’s Diseasementioning

confidence: 99%

PGC-1s in the Spotlight with Parkinson’s Disease

Piccinin

Sardanelli

Seibel

et al. 2021

IJMS

View full text Add to dashboard Cite

Parkinson’s disease is one of the most common neurodegenerative disorders worldwide, characterized by a progressive loss of dopaminergic neurons mainly localized in the substantia nigra pars compacta. In recent years, the detailed analyses of both genetic and idiopathic forms of the disease have led to a better understanding of the molecular and cellular pathways involved in PD, pointing to the centrality of mitochondrial dysfunctions in the pathogenic process. Failure of mitochondrial quality control is now considered a hallmark of the disease. The peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1) family acts as a master regulator of mitochondrial biogenesis. Therefore, keeping PGC-1 level in a proper range is fundamental to guarantee functional neurons. Here we review the major findings that tightly bond PD and PGC-1s, raising important points that might lead to future investigations.

show abstract

Hypermethylation of the Gene Coding for PGC-1α in Peripheral Blood Leukocytes of Patients With Parkinson’s Disease

Cited by 19 publications

References 31 publications

DNA methylation of PGC-1α is associated with elevated mtDNA copy number and altered urinary metabolites in Autism Spectrum Disorder

DNA methylation of PGC-1α is associated with elevated mtDNA copy number and altered urinary metabolites in Autism Spectrum Disorder

Epigenetics in Lewy Body Diseases: Impact on Gene Expression, Utility as a Biomarker, and Possibilities for Therapy

PGC-1s in the Spotlight with Parkinson’s Disease

Contact Info

Product

Resources

About