A recent study by researchers at the Central University of Punjab found abnormal platelet activity in Parkinson’s disease (PD). Using the neurotoxin — rotenone — to simulate PD conditions, researchers shed light on why PD patients have a lower risk of ischaemic strokes and heart attacks, by focusing on the role of platelets in thrombosis.
Our body is a complex system where all organs are interconnected. When one organ is affected, it can impact the functioning of others. For example, have you ever experienced a headache while suffering from acidity?
Though the example above may seem trivial, a recent study by the team of researchers at the Central University of Punjab revealed that Parkinson’s disease (PD), a neurodegenerative disorder, affects the function of platelets. Primarily present in blood, platelets are responsible for hemostasis (cessation of bleeding from a blood vessel).
PD is a progressive neurodegenerative disorder that affects dopaminergic neurons, responsible for dopamine synthesis in the brain. Dopamine, often referred to as the “feel-good hormone,” plays a crucial role in regulating the Autonomic Nervous System (ANS), which controls involuntary bodily functions such as heart rate, blood pressure, and respiration. The depletion of dopamine in PD can significantly impact these functions.
Clinical studies have shown that individuals with PD have lower incidence rates of ischemic brain strokes and myocardial infarction (heart attack). These conditions result from thrombosis, which is the blockage of a blood vessel due to clot formation facilitated by platelets in the blood. Given this, the researchers hypothesised that because PD affects autonomic functions like blood pressure and heart rate, patients could experience some heart-related complications related to platelets as a major player.
When a wound occurs, platelets initially adhere to the collagen of the injured tissue. Upon activation, they release numerous chemicals from their cytoplasmic granules, attracting additional nearby platelets to the area to create a clot. Platelets also interact with fibrin to create a fibrinogen mesh that helps to halt bleeding.
Researchers imagined that certain changes in platelets might protect PD patients from experiencing ischemic brain strokes and heart attacks, given the crucial role of platelets in clot formation. Samir Kumar Beura, a PhD researcher at the Central University of Punjab and the lead author of the study, says,
We use rotenone, a neurotoxin that selectively damages dopaminergic neurons, to treat platelets and induce PD-like conditions in vitro. We then evaluated four major functional parameters of platelets: adhesion, activation, degranulation, and aggregation.
Researchers tested different platelet functional parameters affected by rotenone using various experimental methods. They assessed the adhesion of platelets using a nitrophenol-based adhesion assay and microscopic methods. Platelet activation was evaluated by exposing antibodies targeting the open conformational form of the GPIIb/IIIa receptor, a marker for activated platelets, using a flow cytometer and confocal microscope. Similarly, the degranulation was measured with P‑selectin targeting antibodies using a flow cytometer and confocal microscope. Finally, they used an aggregometer and phase-contrast microscopy to assess platelet aggregation capabilities.
Sunil Kumar Singh, Associate Professor, Department of Biochemistry, Central University of Punjab, says, “Our findings show that the platelet function is reduced in a rotenone-treated sample of platelets. If we correlate our results with PD, it supports the fact that aged PD patients should have a lower incidence of ischemic strokes and heart attacks, as platelets in these patients are less efficient in clot formation.”
The question that remained was: why would a neurotoxin cause reduced platelet functions?
To address this, researchers investigated the molecular mechanisms behind decreased platelet activities. It is evident that reactive oxygen species (ROS) are often observed to modulate the platelet functions.They discovered elevated levels of ROS and hypothesised that these were generated through the IP3R‑Ca2+-PKC-NOX signalling pathway. This hypothesis was validated by deactivating each element of the pathway and observing the impact on ROS generation. For example, when all Ca2+ was sequestered, ROS production significantly decreased.
Patrick D’Silva, Professor, Indian Institute of Science (IISc), Bangalore, and an expert in the field, adds, “This research offers new insights into the abnormal platelet function in PD, potentially illuminating the molecular underpinning of platelet alteration observed in PD patients.”