Gene therapy delivered to a novel mouse model of Parkinson's disease improved the effects of existing Parkinson's drug levodopa.
In Parkinson's disease, the death of brain cells called neurones which produce the neurotransmitter dopamine results in problems with motor control. Making dopamine requires a lot of energy, placing demands on the neurones' mitochondria, which may increase their vulnerability to mitochondrial dysfunction. Loss of mitochondrial complex I is a hallmark of Parkinson's disease, but it was previously unclear whether this dysfunction was a side effect or a cause of Parkinson's disease pathology.
A study by researchers from Northwestern University in Evanston, Illinois has revealed the role mitochondrial dysfunction may play in Parkinson's disease. Study lead Professor D James Surmeier said: 'This is the first time there has been definitive evidence that injury to mitochondria in dopamine-releasing neurones is enough to cause a human-like parkinsonism in a mouse.'
In the study published in the journal Nature, researchers deleted a critical subunit of mitochondrial complex I in the mouse, thus disrupting mitochondrial function in the neurons that create dopamine. The researchers then monitored the mice as they aged, to determine the role of mitochondrial dysfunction in Parkinson's disease progression. The mice first exhibited some motor and learning deficits that coincided with a loss of dopamine signalling in the dorsal striatum region of the brain, which is known to be affected in patients with Parkinson's disease. However, the mice did not start to display classic Parkinson's disease motor deficits until later, specifically when dopamine release from the substantia nigra part of the brain was reduced.
It has been known for some time that the drug levodopa becomes less effective in patients with Parkinson's disease as the disease progresses and more dopamine-producing neurones are lost. The researchers delivered a gene therapy using a viral vector to the substantia nigra, which made neurones in that region express an enzyme that converts the Parkinson's drug levodopa to dopamine. The therapy restored the dopaminergic neurones' ability to convert levodopa into dopamine, and thus rescued the motor deficits.
The researchers claim that their model of Parkinson's disease, with its slow, progressive loss of neurones that create dopamine contrasting with conventional Parkinson's disease models which assume the disease is caused by rapid depletion of dopamine, could allow them to investigate what is happening in the brain before clinical symptoms appear.
Professor Surmeier said: 'This new 'human-like' model may help us develop tests that would identify people who are on their way to being diagnosed with Parkinson's disease in five or ten years... Doing so would allow us to get them started early on therapies that could alter disease progression.'
Sources and References
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Disruption of mitochondrial complex I induces progressive parkinsonism
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Gene therapy boosts Parkinson's disease drug benefits
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This small gene edit in the brain could stop Parkinson's
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Mouse study offers hope for gene therapy against Parkinson's disease
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Gene therapy bolsters Parkinson's drug benefits in pre-clinical study
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Gene therapy could make Parkinson's drug more effective
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