Study offers insight into how sex differences affect Parkinson’s
Understanding sex differences could help develop more personalized treatments
Male and female mice show different responses to toxic alpha-synuclein clumps, a hallmark of Parkinson’s disease, with males experiencing faster and more aggressive neurodegeneration and females showing earlier brain damage before motor symptoms appear, a study has found.
Understanding these sex differences could help develop better, more personalized treatments for Parkinson’s and other synucleinopathies in men and women. Synucleinopathies are neurodegenerative diseases characterized by abnormal deposits of the alpha-synuclein protein.
“Our study significantly contributes to the expanding body of knowledge, offering insights that could profoundly impact the design and implementation of sex-specific therapeutic interventions for synucleinopathies,” researchers wrote.
Their study, “Female mice exhibit resistance to disease progression despite early pathology in a transgenic mouse model inoculated with alpha-synuclein fibrils,” was published in Communications Biology.
In Parkinson’s, the alpha-synuclein protein becomes prone to clumping into threadlike structures called fibrils. These fibrils assemble into Lewy bodies that are toxic to dopaminergic neurons, or nerve cells that produce dopamine, which is a chemical needed for motor control. The gradual loss of dopaminergic neurons results in motor symptoms associated with the disease.
More men than women are diagnosed with Parkinson’s
Like other synucleinopathies, Parkinson’s appears to show in different ways in men and women. The disease also develops and is diagnosed about twice as often in men than in women, with earlier research suggesting that women may mount a better immune response against toxic alpha-synuclein clumps.
To better understand these sex differences, the researchers used mice carrying a disease-causing mutation in one copy of the gene coding for alpha-synuclein as a model of Parkinson’s. These mice don’t usually show any motor symptoms until about 2 years of age.
Mice were injected with preformed fibrils into the dorsal striatum, which can make alpha-synuclein build up faster and cause motor symptoms sooner. The dorsal striatum is a region of the brain that helps control movement. Some mice served as controls and were injected with a saline solution (placebo).
Compared with the control mice, those injected with the preformed fibrils didn’t survive as long, with the males surviving an average of 23 days after showing motor symptoms, which was less than the female mice. This suggests that males and females respond differently to toxic alpha-synuclein clumps.
Contrary to earlier research, however, there were no significant differences in how early male and female mice showed the first motor symptoms. No differences were also observed in how well male and female mice performed on motor tasks like running on a rotating rod, hanging from a wire, or going down a pole.
MRI shows male mice experienced faster neurodegeneration over time
When the researchers looked at brain MRI scans of the model mice, they observed that males experienced faster neurodegeneration over time compared with females, especially in regions like the dorsal striatum and the substantia nigra, both of which are affected in people with Parkinson’s.
However, at about three months after injection of the preformed fibrils, neurodegeneration affected a wider area of the brain of females, suggesting “there is a more spatially widespread neurodegeneration pattern for the female mice compared to their male counterparts,” the researchers wrote.
These findings showed that while male mice didn’t survive as long, perhaps due to “more aggressive neurodegeneration,” female mice showed earlier signs of neurodegeneration on brain MRI scans before motor symptoms developed.
“Our findings not only underscore the importance of considering sex … differences in synucleinopathies but also reveal a gap in the existing literature,” the researchers wrote, noting that this is valid for both “research and clinical practice.”
“Future research should aim to investigate the molecular and cellular mechanisms driving sex differences in synucleinopathy [disease mechanisms], as it may offer significant implications for patient management and the development of targeted therapeutic interventions,” they wrote.
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