Changes in Gene Activity May Cause Disease to Affect Sexes Differently
Disease and rigidity more common in men, tremors more often seen in women
The activity of multiple genes in the brain varies according to sex among people with Parkinson’s disease, a new study reports.
These differences may contribute to discrepancies in how Parkinson’s tends to affect men and women. “While males have a higher age-adjusted disease incidence and are more frequently affected by muscle rigidity, females present more often with disabling tremors,” its researchers noted.
Many of these genes are involved in biological processes previously linked to Parkinson’s, and some have been proposed as potential treatment targets.
The study, “Systems level analysis of sex-dependent gene expression changes in Parkinson’s disease,” was published in npj Parkinson’s Disease.
Analysis looks at differences in activity, according to sex, of 1,264 genes
Biological sex has a marked effect on how Parkinson’s develops and progresses. Men are up to twice as likely to develop the disease and are more likely to experience muscle rigidity as a Parkinson’s symptom, whereas women are more likely to experience tremors and complications related to treatment.
The reasons for these sex-based differences are poorly understood. To learn more, a trio of researchers in Luxembourg conducted a meta-analysis, a type of study where scientists pool and collectively analyze data from multiple studies.
Specifically, this work focused on datasets of gene expression in samples of brain tissue collected after death from people with Parkinson’s and matched adults without the disease as controls. Gene expression refers to how much individual genes are “turned on or off” in terms of their activity.
“The meta-analysis allowed us to identify more significantly differentially expressed genes than when using the individual datasets in isolation,” the researchers wrote.
They assessed nearly 12,000 genes, looking for those whose activity levels were significantly altered in patients versus controls according to sex. They identified 1,146 differentially expressed genes (DEGs) in men with Parkinson’s and 118 DEGs in female patients.
Partly, the higher number of DEGs in men could be due to the larger number of male samples included in the analysis, allowing greater statistical power to identify significantly altered gene activity, the researchers noted.
However, analyses involving a subset of the men also generally yielded higher numbers of genes with altered activity. As such, “the lower number of significant DEGs in females may at least partly reflect a different disease manifestation and progression,” the team wrote.
The scientists divided the DEGs into three categories: 36 were female specific, meaning significant activity changes were detected in women only, while 539 were male specific. Another 37 DEGs were sex dimorphic, meaning they showed opposite trends between sexes (higher levels in women but lower levels in men, or vice versa).
Changes seen in activity of genes linked to dopamine and mitochondria
Many of the genes identified in these analyses “are involved in cellular processes and organelles previously described to display pathological [disease-driving] alterations in PD [Parkinson’s disease],” the researchers wrote.
For example, several of these genes are involved in the production of dopamine or the function of mitochondria, the cell’s powerhouses, and lysosomes, the cell’s recycling centers. Dopamine is the major brain chemical messenger that’s progressively lost in Parkinson’s, while mitochondrial damage and lysosomal impairment have been implicated in the disease.
Further analyses were conducted to assess the biochemical pathways most affected by these gene activity changes. Results indicated that male-specific and sex-dimorphic DEGs were commonly involved in mitochondrial function and cellular energy metabolism, while female-specific DEGs more commonly associated with inflammation.
“No significant overlap was observed between the pathways with female DEGs and male DEGs, suggesting that instead of affecting different genes in the same pathways, sex-specific changes tend to affect diverse pathways,” the team wrote.
While many of the DEGs have known functions in Parkinson’s-related pathways, most have not been specifically linked to Parkinson’s before.
Notably, one exception was the NR4A2 gene, whose activity was generally lower in Parkinson’s patients relative to controls, but the effect was much more pronounced in men.
This gene has a “key regulatory role in the maintenance of dopamine metabolism and inflammatory gene expression,” the researchers wrote, and its reduced activity has been linked to brain aging and increased production of the alpha-synuclein protein, a hallmark of Parkinson’s.
Preclinical work has implicated NR4A2 activity changes in Parkinson’s and suggested that the protein it encodes may be a useful treatment target.
“Given the prior evidence for the druggability of NR4A2, the beneficial effects of its activation in PD model systems, and the sex-dependent changes among its downstream target genes, the protein may warrant further investigation as target for pharmacological modulation of a subset of pathological molecular changes in PD that display sex-associated activity profiles,” the team wrote.
Two other sex-dependent DEGs of interest with Parkinson’s-associated regulatory functions were CA2 and EFNA1. CA2 is involved in mitochondrial function and its increased activity in patients compared with matched controls was “significantly stronger in females than in males,” the researchers wrote.
EFNA1, “the most significant sex-dimorphic gene,” is known to play a role in the development of the nervous system, including dopamine-producing neurons.
Further research will “be needed to more comprehensively characterize and confirm the mechanisms by which NR4A2 and other regulatory genes control or modulate the identified molecular sex differences” seen in Parkinson’s, the researchers wrote.
“If the druggability, sex-dependency, and neuroprotective roles of NR4A2 or other candidate targets can be further substantiated, this could pave the way for subsequent preclinical investigations of [treatment] strategies to reduce or alleviate sex-dependent molecular pathology in PD,” they concluded.
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