Brain cell changes may explain why Parkinson’s affects more men than women

Males are around 1.5 times more likely to develop Parkinson’s disease than females. Additionally, females tend to develop the condition later than males and survive for longer.

These differences could be due to a range of factors, including an increased likelihood of men experiencing head injuries or exposure to pesticides, solvents, and metals.

However, it is still an open question, and the latest study helps us begin to answer it.

The new study approaches the condition from a new angle. “The most interesting aspect is that the researchers are examining Parkinson’s disease through the lens of biological sex and glial cells, rather than focusing only on neurons,” Laura Bojarskaite, PhD, told Medical News Today. Bojarskaite, who was not involved in the study, is a neuroscientist and postdoctoral fellow at the University of Oslo.

In particular, the researchers investigated epigenetics and their potential role in the sex differences seen in Parkinson’s. Epigenetic changes are not changes to the DNA code; rather, they are modifications that switch genes “on” or “off.”

The most well-studied form of epigenetic modification is methylation, in which a methyl group is added to DNA, effectively switching it “off” or “silencing” it.

Lead author Prof. Julia Schulze-Hentrich’s previous research showed that females with Parkinson’s had changes to DNA methylation in 69 regions of their genome. In males, however, only two regions were affected.

As she explains, this suggests “that a person’s genetic make-up influences these DNA methylation changes.” This spurred her to investigate what specifically might influence differences in DNA methylation patterns between males and females.

Schulze-Hentrich and her colleagues collected brain samples from deceased people. In total, there were 73 people with Parkinson’s (28 females and 45 males). They compared these samples with 24 individuals without Parkinson’s (9 females and 15 males).

The scientists measured differences in gene expression across all brain cell types in five regions. This includes neurons, which transmit messages, and glial cells, which are multi-functional support cells for neurons. Glial cells include astrocytes, oligodendrocytes, and microglia.

“We studied five brain regions and found that Parkinson’s causes common changes in the brain, regardless of sex,” explains Schulze-Hentrich. “

“All these cells in the five regions,” she continued, “showed signs of being under stress. They switched on proteins that help damaged proteins fold correctly, called ‘chaperones.'”

Interestingly, they also found differences in gene activity between males and females, in some cells and some brain regions.

Schulze-Hentrich and her team identified differences in gene activity between the sexes, including:

• In astrocytesdifferences in the activity of genes associated with mitochondria (cell organelles that produce energy).
• In oligodendrocytesthere were differences in the activity of genes responsible for creating the brain cells’ myelin sheath, which is a protective coating necessary for signal transduction.

“This shows that Parkinson’s triggers some shared ‘stress responses’ in everyone’s brain cells,” explains Schulze-Hentrich, “but also, there are differences between men and women at the cellular level, especially in how the brain ‘support’ cells manage energy and protect nerve connections.”

She explains how their findings “help to explain why symptoms and disease progression in Parkinson’s differ between men and women.”

She hopes that this could, eventually, lead to personalized Parkinson’s treatments, “rather than treating all patients with Parkinson’s as biologically identical.”

Speaking to MNTDr. Kang Hsu, Chief Medical Officer (CMO) of Canary Speech, said, “What stands out most to me is that women with Parkinson’s showed stronger blood-based gene-switch changes than men, even though men get Parkinson’s more often.” Hsu was not involved in the investigation.

In the past, much of the research on Parkinson’s disease has focused only on neurons or on males (humans or animals). Schulze-Hentrich hopes that future researchers will cast their net a little wider, helping us better understand the individual differences in how this condition develops and progresses.

This study adds a small piece to the huge, sprawling jigsaw that is Parkinson’s disease. Despite the condition being named well over 100 years ago, we are still far from a cure, and existing treatments are still limited.

MNT asked neurologist, Dr. Rab Nawaz Khan, who was not involved in the study, why Parkinson’s is so challenging to study:

“Parkinson’s likely begins years before the classic movement symptoms appear, making it difficult to know when the disease truly started or which exposures mattered most.”

“It is also a very heterogeneous condition,” he continued, “two people can have different symptoms, rates of progression, genetic backgrounds, and environmental histories.” Plus, he explains, “We still lack a simple, definitive test that can identify every case early.”

“Environmental exposures, inflammation, and lifestyle all contribute to risk, but their relative importance differs between individuals. Rather than being caused by a single factor. Parkinson’s likely results from the interaction of many biological and environmental influences, making it difficult to pinpoint clear causes.”
—Laura Bojarskaite, PhD

So, while the new study adds to our understanding, we still have a long journey ahead of us.