Neurological disorders are the leading cause of disability worldwide, and Parkinson’s disease is among the most prevalent brain disorders in humans, with diagnosis rates doubling in the last 25 years. As a neurological disorder, Parkinson’s disease is characterized by the loss of nerve cells (neurons) in the brain, which result in a patient experiencing a range of motor-related symptoms, including slowed movement (bradykinesia), muscle tremors, and instability while standing or walking, as well as non-motor symptoms, such as difficulty focusing and thinking, gastrointestinal problems and sleep problems. By 2040, Parkinson’s disease is projected to affect 13 to 14 million people annually, in what researchers are referring to as an impending pandemic.
In a patient with Parkinson’s disease, neurons within the regions of the brain called the basal ganglia and substantia nigra die at alarmingly high rates. These dying cells often release the neurotransmitter dopamine, and when 50–80 percent of these dopamine-releasing (dopaminergic) neurons are lost, the symptoms of Parkinson’s disease occur. Therefore, understanding what biological mechanisms cause dopaminergic neurons to degenerate is important for establishing treatments to slow or prevent the onset of this disorder.
It is this mechanism that a team of researchers within the Neuroscience & Experimental Therapeutics department at the Texas A&M University School of Medicine have spent years studying, recently publishing their findings in the scientific journal Glia. This team, led by Eric Bancroft, PhD, within the laboratory of Rahul Srinivasan, PhD, is the first to propose that a specific, detrimental relationship between dopaminergic neurons and a second type of cell in the brain—called astrocytes—underlies the neuronal death associated with Parkinson’s disease.
“In this study, we show that cell extensions from astrocytes completely cover the cell bodies of dopaminergic neurons in our brain,” Srinivasan said. A picture showing this relationship is featured on the cover of Glia for the December 2022 issue. “This novel relationship between astrocytes and dopamine neurons strongly suggests that proteins secreted by astrocytes are perfectly positioned to directly affect the function of the dopaminergic neurons.”
But what makes these astrocytes such a threat to dopaminergic neurons? Srinivasan explains, “We show that S100B, a protein secreted by astrocytes, abnormally changes the activity of dopamine neurons, leading to the death of dopamine neurons and the development of Parkinson’s disease.” This finding is particularly compelling because patients with Parkinson’s disease are already known to have abnormally high levels of S100B in the fluids surrounding their brain, as well as specifically within the substantia nigra. Furthermore, previous research has demonstrated that increased levels of S100B in the brain contribute to the death of nearby dopaminergic neurons. Therefore, this study is well-supported by existing literature, Srinivasan said, and, in turn, explains previous findings from clinical studies in patients with Parkinson’s disease.
Currently, there is no cure for this common neurological disorder. Existing clinical therapeutics are often prescribed to treat the symptoms of Parkinson’s disease, rather than the cause, due to the uncertainty surrounding the exact source of this condition. This is where Bancroft’s research fills an important knowledge gap in the field.
“We have found a very specific mechanism of interaction between a protein secreted by astrocytes (S100B) and a specific receptor on dopamine neurons (voltage gated potassium channels),” he said. “We believe that this abnormal interaction between S100B and target potassium channels on dopamine neurons can be blocked by drugs, which would slow down or even stop the loss of dopamine neurons during the earliest stages of Parkinson’s disease.”
Although this research is foundational and impactful on its own, the next stage of this investigation, Srinivasan and Bancroft said, is to incorporate these findings into the development of drugs that prevent astrocyte-originating S100B from interacting with voltage gated potassium channels on dopaminergic neurons. According to Srinivasan, “This will require us to screen compounds, and in the coming years, identify lead drugs to bring to the clinics as a first-in-class drug therapeutic to slow down the loss of dopamine neurons in Parkinson’s disease.”
Srinivasan, whose lab in the School of Medicine is devoted to the investigation of neurodegeneration and to the subsequent development of pharmacological treatments, praised his lab members for their commitment to rigorous science. “This study would not have been possible without the first author Eric Bancroft, who systematically and meticulously performed all the experiments as a part of his graduate work,” Srinivasan said. “Co-authors Martha De La Mora, a talented Texas A&M undergraduate student, and graduate students Gauri Pandey and Sara Zarate played vital roles in contributing to the success of this very important and exciting study.”