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Potential diagnostic, hope for a Parkinson’s disease treatment

A new discovery could provide a way of detecting Parkinson's disease in its earliest stages, before symptoms start. And it could accelerate the development of a drug capable of halting the progression of this debilitating condition.

In a study published in Cell Metabolism, Stanford neuroscientist Xinnan Wang, MD, PhD, and her colleagues have pinpointed a cellular defect that seems to be both near-universal among Parkinson's patients and exclusive to them. From my news release about the study:

Parkinson's, the second most common neurodegenerative disease, affects 10 million people worldwide. Some 5%-10% of cases are familial -- the inherited result of known genetic mutations. But the vast majority are sporadic, involving complex interactions of multiple unknown genes and environmental factors.

So it's promising that the diagnostic marker -- a test for Parkinson's defining cellular defect -- flagged both the familial and sporadic versions of the condition. A compound Wang's team applied to cells from patients proved able to correct this defect in both versions, as well.

No current treatments for Parkinson's address its underlying cause.

An age-related progressive movement disorder, Parkinson's stems from the mysterious die-off of a set of mid-brain nerve cells, or neurons, in the brain that fine-tunes bodily movement. These neurons are referred to as dopaminergic because they secrete a substance, dopamine, to transmit motion-modulating signals to other neurons. By the time a person starts manifesting symptoms of the disease, an estimated 50% of these particular dopaminergic neurons have already died. Again, from my release:

What makes these particular neurons die is unknown. A leading theory holds that the special intensity with which they perform their duties frazzles their mitochondria. These bacteria-sized cellular components generate energy for cells in exchange for a steady supply of raw materials: oxygen and carbon-rich carbohydrates or fats.

But this process, known as respiration, inevitably generates toxic byproducts that not only can cause cellular damage but are extremely harmful to the mitochondria themselves. Like old cars that can no longer pass a smog test because they can't stop spewing noxious exhaust fumes, defective mitochondria have to be taken off the road. Our cells have ways of doing that. But it's complicated.

Wang's group focused on a mitochondrial-clearance defect they found in cells from Parkinson's patients and asymptomatic close relatives at high risk of getting it -- but in no one else, including patients diagnosed with other movement disorders.

Extracting mid-brain dopaminergic neurons -- or, frankly, any kind of brain cells -- from a human brain for a lab experiment -- is nontrivial, to say the least. But every cell in a person's body shares the same DNA. So instead, the researchers worked with fibroblasts -- a cell type that's common in skin tissue and easy to culture in a lab dish -- from Parkinson's patients, their high-risk relatives, patients with other movement disorders and healthy control subjects.

Next, the investigators screened 6,835,320 small molecules using software that predicted which ones would correct the cellular defect -- and would also be nontoxic, orally available and able to cross the blood-brain barrier. One particularly promising compound substantially improved mitochondrial clearance in Parkinson's patients' fibroblasts.

Using now-standard laboratory techniques, Wang and her colleagues converted fibroblasts of Parkinson's patients and healthy controls into dopaminergic neurons. Parkinsonian neurons incubated with the experimental compound rivaled healthy neurons in their ability to rid themselves of burned-out mitochondria.

Wang thinks clinical trials of the compound or a close analog are no more than a few years off. "Our hope," she told me, "is that, if we can give it, like a statin drug, to people who've tested positive for the defect but don't yet have Parkinson's symptoms, they'll never get it."

Photo by Norbert von der Groeben

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