Exosomes: a new biomarker in Parkinson’s?
Original article: Utility of Neuronal-Derived Exosomes to Examine Molecular Mechanisms That Affect Motor Function in Patients With Parkinson Disease: A Secondary Analysis of the Exenatide-PD Trial: JAMA Neurology, 2019.
A secondary analysis of the exenatide clinical trial in Parkinson’s data has reported changes in messenger proteins released by neurons that can be detected in a blood sample. These molecular changes were predicted given our knowledge of exenatide and they are related to insulin signaling, but being able to detect them in blood – and the fact that they were associated with the degree of symptom improvement seen on the drug – represents a potentially powerful new tool for clinical trials of neurodegenerative conditions.
Why is it important?
This study highlights a new potential biomarker, obtained through blood, which could help researchers establish whether a drug has actually reached its target in the brain.
Many types of cells in the body, including neurons, release small sacks, or vesicles, containing a range of different molecular messages as a means of communicating with other cells. Exosomes are one particular type of extracellular vesicles. Once released, they can cross the blood-brain barrier and travel around the body in the blood, carrying messages to distant tissues. This opens up the possibility of getting important insights into the molecular state and function of neurons by analyzing exosomes through a simple blood sample.
Recently, the antidiabetic drug exenatide was trialled in Parkinson’s and shown to improve movement-related function which was sustained even after the drug had been stopped for 12 weeks. Part of the assessments that the 60 people with Parkinson’s who participated in this trial had included having blood samples taken. These blood samples have since been analysed in order to ask whether and what kind of changes could be detected in exosomes as a result of exenatide, and whether a relationship to motor improvement could be detected.
Using different biochemical methods, exosomes which were specific to neurons were isolated from the blood samples of the original group of participants, half of whom received exenatide and the other half received a placebo. Given that exenatide acts on insulin pathways, the team predicted that compared to the placebo group, exosomes from patients who had received exenatide should show greater increases in signaling molecules involved in insulin-related pathways, which we also know promote neuronal survival.
Exosomes from blood taken after 48 weeks of exenatide treatment showed increases in markers of three important cellular pathways involved in insulin signaling, which correlated with the degree of symptom improvement. One of these pathways enhanced on exenatide, called mTOR, also predicted lasting symptom improvement after the drug was stopped.
It will be important to answer a few more open questions, including whether the exosomes were truly derived from neurons as other types of cells can release them as well, and whether these changes reflect events occurring in the brain or other events that these small mobile packages may have encountered elsewhere in the body.
Where can I learn more?
Link to commentary on this work: https://jamanetwork.com/journals/jamaneurology/article-abstract/2719820
Original article: Athauda D, MGulyani, S., Karnati, H., Li, Y., Tweedie, D., Mustapic, M., . . . Foltynie, T. 2019. Utility of Neuronal-Derived Exosomes to Examine Molecular Mechanisms That Affect Motor Function in Patients With Parkinson Disease: A Secondary Analysis of the Exenatide-PD Trial: JAMA Neurology.