Alterations in epigenetic marks found in Parkinson’s patients: Study

Potentially environmentally-driven modifications detected in blood

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by Steve Bryson, PhD |

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Potential environmentally-driven alterations in certain epigenetic marks — DNA modifications that control gene activity — were detected in the blood of people with newly diagnosed, treatment-naïve, sporadic Parkinson’s disease, a study revealed.

These epigenetic marks were linked with cellular processes driving ongoing neurodegeneration that underlies Parkinson’s, and changed over time.

According to the researchers, from Northwestern University Feinberg School of Medicine, in Illinois, these findings show the potential to use such DNA modifications as a biomarker for the neurodegenerative disease.

“It’s a significant step towards unraveling the complex interactions at play in Parkinson’s disease and could pave the way for pinpointing potential biomarkers for early detection and progression,” Paulina Gonzalez-Latapi, MD, assistant professor in the department of neurology’s division of movement disorders and the study’s lead author, said in a university press release.

The study, “Alterations in Blood Methylome as Potential Epigenetic Biomarker in Sporadic Parkinson’s Disease,” was published in the Annals of Neurology.

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Parkinson’s symptoms arise from the progressive loss of nerve cells that produce dopamine, a chemical messenger in the brain. In sporadic cases, it’s not known exactly what triggers the death of these cells, but growing evidence supports a combination of genetic predisposition and environmental factors.

Epigenetic processes — the chemical modifications to DNA that control gene activity without altering the DNA sequences — can be viewed as mediators between genes and the environment. An epigenetic mechanism that turns off gene activity is DNA methylation, or adding a methyl chemical group to cytosine (C), one of the building blocks of DNA.

“DNA methylation in some ways serves as a memory of prior environmental exposures that ultimately alter methylation signatures in our cells and body,” Gonzalez-Latapi said.

Some studies suggest that DNA methylation patterns, called methylome, in the blood differ between people with Parkinson’s and healthy individuals.

In this report, researchers further investigated the DNA methylation differences between individuals with newly diagnosed sporadic Parkinson’s and healthy controls. The team specifically focused on how these differences affect gene activity, and how they changed over time.

“The characterization of DNA methylation and gene expression patterns in blood holds the potential to help us understand complex interactions between environmental and genetic factors in development of Parkinson’s disease,” said Dimitri Krainc, MD, PhD, study lead at Northwestern.

The study included 196 Parkinson’s patients and 86 age- and sex-matched healthy controls from the Parkinson’s Progression Markers Initiative (PPMI). Launched in 2010, the PPMI’s goal is to identify biological markers of Parkinson’s risk, onset, and progression. The initiative enrolls newly diagnosed, treatment-naïve patients, and prodromal (pre-symptomatic) and healthy individuals.

“[Parkinson’s] patients were medication-naïve at the initial assessment, allowing us to identify [DNA methylation] changes that are more plausibly linked to the pathophysiology of the disease itself, rather than to pharmacological interventions,” the researchers noted.

The characterization of DNA methylation and gene expression patterns in blood holds the potential to help us understand complex interactions between environmental and genetic factors in development of Parkinson’s disease.

Analysis of DNA extracted from whole blood samples at the study’s start, or baseline, found that, compared with controls, newly-diagnosed Parkinson’s patients had 2,683 instances of increased methylation (hypermethylation) and 2,495 instances of decreased methylation (hypomethylation).

Many of these differentially methylated positions, or DMPs, were found near the CYP2E1 gene, which provides instructions for an enzyme that helps break down many substances, including toxic environmental chemicals.

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The researchers then focused on differentially methylated regions, or DMRs, which consist of clusters of contiguous DMPs that are thought to be functional areas involved in gene activity regulation. At baseline, 13,071 DMRs were identified between patients and controls, many associated with nerve cell functions, including those associated with dopamine.

At the same time, 71 genes were more active, or upregulated, and four genes were less active, or downregulated, in blood samples from Parkinson’s patients versus controls. Among them, 20 genes showed reduced methylation that paralleled an increase in related gene activity.

The CTSH gene was hypermethylated at baseline and significantly less active in Parkinson’s patients, the researchers noted. CTSH encodes cathepsin H, an enzyme that helps break down damaged or unwanted proteins in lysosomes, the cell’s recycling compartments. Lysosomal defects have been implicated in Parkinson’s development and progression.

Over three years, 579 DNA positions underwent significant methylation changes in the Parkinson’s group, which were associated with “critical biological pathways.”

Again, the CYP2E1 gene stood out and was noted to be hypomethylated, meaning there was greater gene activity and more enzyme production. Meanwhile, the NDRG4 gene was hypermethylated, a state associated with cancer due to the dysfunction of energy-producing mitochondria. In people with Parkinson’s, damage to mitochondria is evident before the onset of symptoms, previous research has shown.

According to the researchers, the study “provides evidence that alterations in the methylome [methylation patterns] in [Parkinson’s] are discernible in blood, evolve over time, and reflect cellular processes linked to ongoing neurodegeneration.”

“These findings lend support to the potential of blood [methylome] as an epigenetic biomarker for [Parkinson’s],” the team wrote.

Krainc added, “From a broader perspective, such patient-based studies will help categorize Parkinson’s disease patients through a biological lens that will ultimately facilitate the development of more precise treatments for patients with different subtypes of disease.”

Gonzalez-Latapi is supported by a PPMI Early Investigator Award.