Parkinson’s disease (PD) is a progressive neurodegenerative disorder primarily associated with an inability to initiate and control voluntary movement.
The onset of Parkinson’s disease is caused by a loss of dopamine neurons in the midbrain. While it is unknown what causes this neuron loss, being male has always been linked as one of the strongest risk factors to developing the disease.
Men are twice as likely to develop PD as women and the progression of the disease is more rapid in men. Traditionally, sex differences in PD have been attributed to the protective actions of estrogen in females.
However, the finding of this pre-clinical study by Dr Joohyung Lee and Professor Vincent Harley, published in the prestigious Proceedings of the Natural Academy of Sciences, show for the first time that a gene called SRY on the male Y chromosome exacerbates risk factors as well as disease progression in males.
Remarkably, the researchers found that when they lowered the expression of the SRY gene by using synthetic gene therapy, they found reduced dopamine neuron loss and diminished motor symptoms in males.
Their study is a world first in identifying a male-specific therapeutic target for a neurological disease.
Prof Harley said, “Currently, PD therapies only treat symptoms and do not halt or slow the disease.
“Male and female brains are different at all levels: molecular, cellular and behavioural. That’s why we believed it was important to explore potential sex genetic related causes of the disease,” he said.
Study findings
In adult males, the SRY gene controls how the brain functions. SRY proteins regulate the synthesis of dopamine which controls voluntary movement.
The research team led by Dr Lee and Prof Harley found that males with PD produced an abnormally high amount of the SRY protein in their mid-brain.
Dr Lee said, “In the healthy adult male brain, the SRY gene functions to control dopamine neurons and dopamine synthesis. However, we think that in cases of PD, when the male brain starts losing dopamine neurons, the SRY gene tries to compensate by producing more dopamine.
“This over production of dopamine exacerbates inflammation in the male brain,” he said.
The findings suggest that supressing the SRY gene with therapy represents a new sex-specific strategy to slow or prevent dopamine loss for men affected with PD, which would slow down PD progression in men.
Next steps
Dr Lee said, “The next steps in progressing this finding would be to test a range of synthetic gene therapies on human cell culture models. Once we find the most effective therapy, we would then design a novel way to administer the therapy to patients.
“This is a very exciting step towards minimising PD in males,” he said.
Prof Harley said, “We hope our study excites interest in developing SRY-based inhibitors for men with PD.”
Facts: the SRY gene
- At the embryonic stage, the SRY gene initiates male-sex determination by directing the development of the gonads to testes, rather than ovaries.
- In adult human males, the SRY gene is also expressed in non-reproductive tissues, such as the heart, adrenal glands, kidneys and brain.
- The SRY regulates the creation of dopamine neurons which controls voluntary movement.
Collaborators:
University of California, Los Angeles
Funders:
Victorian Government’s Operational Infrastructure, Support Program, Australian NHMRC, CASS foundation, Rebecca L. Cooper Foundation, Helen McPherson Smith Trust and National Institute of Health (NIH) USA.
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