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Epigenome-wide association study of human frontal cortex identifies differential methylation in Lewy body pathology.

ABSTRACT: Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are closely related progressive disorders with no available disease-modifying therapy, neuropathologically characterized by intraneuronal aggregates of misfolded α-synuclein. To explore the role of DNA methylation changes in PD and DLB pathogenesis, we performed an epigenome-wide association study (EWAS) of 322 postmortem frontal cortex samples and replicated results in an independent set of 200 donors. We report novel differentially methylated replicating loci associated with Braak Lewy body stage near TMCC2, SFMBT2, AKAP6 and PHYHIP. Differentially methylated probes were independent of known PD genetic risk alleles. Meta-analysis provided suggestive evidence for a differentially methylated locus within the chromosomal region affected by the PD-associated 22q11.2 deletion. Our findings elucidate novel disease pathways in PD and DLB and generate hypotheses for future molecular studies of Lewy body pathology.

SUBMITTER: Pihlstrom L

PROVIDER: S-EPMC9395387 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Epigenome-wide association study of human frontal cortex identifies differential methylation in Lewy body pathology.

Pihlstrøm Lasse L Shireby Gemma G Geut Hanneke H Henriksen Sandra Pilar SP Rozemuller Annemieke J M AJM Tunold Jon-Anders JA Hannon Eilis E Francis Paul P Thomas Alan J AJ Love Seth S Mill Jonathan J van de Berg Wilma D J WDJ Toft Mathias M

Nature communications 20220822 1

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are closely related progressive disorders with no available disease-modifying therapy, neuropathologically characterized by intraneuronal aggregates of misfolded α-synuclein. To explore the role of DNA methylation changes in PD and DLB pathogenesis, we performed an epigenome-wide association study (EWAS) of 322 postmortem frontal cortex samples and replicated results in an independent set of 200 donors. We report novel differentially m ...[more]

PMID: 35995800

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Project description:ObjectivesThe goal of this study was to assess mitochondrial function, energy, and purine metabolism, protein synthesis machinery from the nucleolus to the ribosome, inflammation, and expression of newly identified ectopic olfactory receptors (ORs) and taste receptors (TASRs) in the frontal cortex of typical cases of dementia with Lewy bodies (DLB) and cases with rapid clinical course (rpDLB: 2 years or less) compared with middle-aged non-affected individuals, in order to learn about the biochemical abnormalities underlying Lewy body pathology.MethodsReal-time quantitative PCR, mitochondrial enzymatic assays, and analysis of β-amyloid, tau, and synuclein species were used.ResultsThe main alterations in DLB and rpDLB, which are more marked in the rapidly progressive forms, include (i) deregulated expression of several mRNAs and proteins of mitochondrial subunits, and reduced activity of complexes I, II, III, and IV of the mitochondrial respiratory chain; (ii) reduced expression of selected molecules involved in energy metabolism and increased expression of enzymes involved in purine metabolism; (iii) abnormal expression of nucleolar proteins, rRNA18S, genes encoding ribosomal proteins, and initiation factors of the transcription at the ribosome; (iv) discrete inflammation; and (v) marked deregulation of brain ORs and TASRs, respectively. Severe mitochondrial dysfunction involving activity of four complexes, minimal inflammatory responses, and dramatic altered expression of ORs and TASRs discriminate DLB from Alzheimer's disease. Altered solubility and aggregation of α-synuclein, increased β-amyloid bound to membranes, and absence of soluble tau oligomers are common in DLB and rpDLB. Low levels of soluble β-amyloid are found in DLB. However, increased soluble β-amyloid 1-40 and β-amyloid 1-42, and increased TNFα mRNA and protein expression, distinguish rpDLB.ConclusionMolecular alterations in frontal cortex in DLB involve key biochemical pathways such as mitochondria and energy metabolism, protein synthesis, purine metabolism, among others and are accompanied by discrete innate inflammatory response.

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Epigenome-wide association study of human frontal cortex identifies differential methylation in Lewy body pathology.

Publications

Epigenome-wide association study of human frontal cortex identifies differential methylation in Lewy body pathology.

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