Why does Parkinson's affect more men than women? The answer may be estrogen.
Today, approximately 500,000 people in the U.S. are living with Parkinson's disease.
One of the primary risk factors is advanced age, so as the population grows ever older, the number of Parkinson's cases is likely to rise.
Understanding how and why the condition develops is paramount because there is currently no cure.
Alpha-synuclein and Parkinson's
The primary driver of Parkinson's is a mutated, shorter-than-normal version of a protein called alpha-synuclein.
This protein congregates inside the dopamine-producing neurons that are responsible for coordinating movements and forms structures called Lewy bodies and neurites.
Over time, the buildup of alpha-synuclein prevents brain cells from functioning and, eventually, they die. The resultant loss of neurons causes the movement problems that are characteristic of Parkinson's, such as tremor and rigidity.
Although scientists have been studying Parkinson's for decades, there are still many gaps in their knowledge.
One of these unanswered questions is why Parkinson's occurs earlier in men and is more common in postmenopausal women.
Earlier studies identified a relationship between estrogen and Parkinson's disease.
For instance, the authors of a 2004 study investigating Parkinson's risk and its relationship with "reproductive characteristics" concluded that there was "[a]n association between factors reducing estrogen stimulation during life and [Parkinson's disease]."
Other findings over the years have hinted that estrogen might protect the brain. One study recruited women who had undergone an oophorectomy, which is the surgical removal of one or both ovaries, the primary source of estrogen in women.
They found that these women had an increased risk of cognitive decline and Parkinson's disease.
Other studies have found evidence that estrogen might help reduce symptoms of Parkinson's. One small-scale study, for example, found that low doses of estrogen reduced motor symptoms in postmenopausal women with Parkinson's.
Although estrogen's neuroprotective powers are becoming better established, exactly how estrogen might protect against Parkinson's disease is still a mystery.
A new mouse model of Parkinson's
The Harvard researchers used a new mouse model of Parkinson's disease that they first described in 2018. They treated the mice with DHED, a chemical that boosts estrogen levels in the brain.
The researchers compared the motor function of male and female mice before and after treatment. They also looked at how alpha-synuclein was behaving within the brain and the rate of neuron death.
The female mice had less severe symptoms than the male mice, but estrogen treatment still improved their symptoms. In male mice, estrogen slowed the loss of nerve fibers and improved motor symptoms.
The scientists noted that estrogen reduced the buildup of mutated alpha-synuclein by boosting autophagy, which is one of the body's mechanisms for removing cellular debris.
Among other changes, they showed that DHED treatment in male mice increased the number of nerve fibers that produce tyrosine hydroxylase — this enzyme helps convert an amino acid into L-DOPA, a precursor for dopamine. They also noted that these fibers were more abundant in female mice with or without treatment.
In combination with earlier work, these findings bolster the idea that estrogen protects against Parkinson's disease.
They also suggest that estrogen treatment might be beneficial even after symptoms have started, which is important because spotting neurodegenerative conditions before symptoms arise is challenging.
However, as always, the transition from an animal model to clinical trials in humans will be the making or breaking of this theoretical intervention.
The researchers hope that boosting estrogen in human brains might, one day, offer a way to slow Parkinson's disease progression.