Parkinson’s disease expert Valina Dawson, Ph.D., visited NIEHS Sept. 18 to discuss how Parkinson’s attacks the body. Her talk for the Distinguished Lecture Series, "Deciphering the Pathologic Code in Parkinson’s Disease," was hosted by NIEHS Neurobiology Laboratory Deputy Chief Serena Dudek, Ph.D.
Parkinson’s is a progressive neurodegenerative disease, characterized by muscle stiffness and shaking. Although many think of it as an old person’s disease, children as young as six months old can show symptoms of Parkinson’s and be diagnosed as toddlers.
Dawson said that approximately 6 million people worldwide have Parkinson’s and that 15 percent of the human population can inherit the disease.
Parkinson’s destroys nerve cells in the brain, yet Dawson and others in the field theorize that it actually starts in the gut. People who eventually develop Parkinson’s often start out complaining of severe constipation. In fact, some Parkinson’s patients die from sepsis, which is the body’s reaction to an uncontrolled infection, due to constipation.
Dawson suggested that after leaving the intestines, the trigger travels up through the vagus nerve and enters non-motor regions of the brain. As a result, Parkinson’s patients tend to experience severe dementia, anxiety, depression, and a disorder of rapid eye movement sleep.
Dawson said that a small, flexible protein known as alpha-synuclein plays a huge role in the progression of Parkinson’s. Scientists do not know exactly what it does, but they know it is involved in conducting nerve signals.
Because of its structure, alpha-synuclein tends to misfold and produce sticky filaments called fibrils. Fibrils are toxic to the body and can induce normal alpha-synuclein molecules to misfold. When fibrils clump together, they create a pathological feature of Parkinson’s called a Lewy body.
"We think these toxic fibrils get excreted from the neuron they were created in and are ferried to the next neuron," Dawson said. "Once inside the new neuron, the fibrils start to induce the normal alpha-synuclein molecules there to misfold. This process drives the progression of the disease."
Dawson’s lab focus
Dawson uses recombinant, or lab-made, alpha-synuclein to produce fibrils to study. Within six months of injecting fibrils into mice, members of her research group saw a loss of dopaminergic neurons, or brain cells that use the neurotransmitter dopamine.
The researchers also combined recombinant alpha-synuclein with cerebrospinal fluid from Parkinson’s patients and used technology that promotes protein misfolding to create fibrils. When the researchers grew these fibrils in a lab culture, they found that those grown from patients with mild Parkinson’s were toxic, but not as toxic as those from patients who have late-stage Parkinson’s with dementia.
"This suggests there’s something about the way these fibrils are inducing normal alpha-synuclein that drives the specificity and severity of disease," Dawson said.