In human cell cultures, countering a defect that appears to be nearly universal among patients with Parkinson’s disease prevents death in the cells whose loss causes the disease.
Investigators at the Stanford University School of Medicine have pinpointed a molecular defect that seems almost universal among patients with Parkinson’s disease and those at a high risk of acquiring it.
The discovery could provide a way of detecting the neurodegenerative disorder in its earliest stages, before symptoms start to manifest. And it points to the possibility of halting the disease’s progression. The defect appears to be exclusive to individuals with Parkinson’s disease.
“We’ve identified a molecular marker that could allow doctors to diagnose Parkinson’s accurately, early and in a clinically practical way,” said Xinnan Wang, MD, PhD, associate professor of neurosurgery. “This marker could be used to assess drug candidates’ capacity to counter the defect and stall the disease’s progression.”
The scientists also identified a compound that appears to reverse the defect in cells taken from Parkinson’s patients. In animal models of the disease, the compound prevented the death of the neurons whose loss underlies the disease.
These steps are described in a study published online in Cell Metabolism. Wang is the study’s senior author. Postdoctoral scholars Chung-Han Hsieh, PhD, and Li Li, MD, PhD, share lead authorship.
Common neurodegenerative disease
Parkinson’s, the second most common neurodegenerative disease, affects 35 million people worldwide. Whereas 5%-10% of cases are familial — the inherited result of known genetic mutations — the vast majority are sporadic, involving complex interactions of multiple unknown genes and environmental factors.
So it’s encouraging, Wang said, that both the diagnostic marker and the treatment worked in cells from Parkinson’s patients with either familial or sporadic versions of the condition.
An age-related progressive movement disorder, the disease stems from the mysterious die-off of a set of nerve cells, or neurons, in the brain that fine-tunes bodily movement. These neurons, which originate in a midbrain structure, the substantia nigra, 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 the substantia nigra’s dopaminergic neurons have already died.
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.
This process, known as respiration, has a downside: It inevitably generates toxic byproducts called free radicals, which not only can cause cellular damage but are extremely harmful to the mitochondria themselves.