Research carried out in Oxford has led to the development of a new way to test for Parkinson’s disease before the main symptoms occur. This could allow clinicians to identify patients who would benefit from precision therapies that are currently at clinical trial stage.
Parkinson’s disease is the second most common neurodegenerative disease, affecting 10 million people worldwide with significant healthcare and societal impact.
The disease is caused by failure of nerve cells to handle a small protein called alpha-synuclein. This leads to the formation of abnormal clumps of alpha-synuclein which damage vulnerable nerve cells, causing the movement disorder and often dementia. By the time people develop Parkinson’s disease, most of these vulnerable nerve cells have already died and alpha-synuclein clumps form in many brain regions.
It would be useful if we could predict whether the pathways that handle alpha-synuclein are impaired before the onset of Parkinson’s symptoms. This could help us to identify those patients most likely to benefit from therapies that target alpha-synuclein (currently in clinical trial stage). Such a biomarker may also offer a means of monitoring the response to these interventions.
A recent study, led by George Tofaris at the Nuffield Department of Clinical Neurosciences and supported by the NIHR Oxford Biomedical Research Centre, revealed the promise of studying particular extracellular vesicles, called exosomes, to identify changes in alpha-synuclein in people at risk of developing Parkinson’s disease. These vesicles function as cellular ‘envelopes’ that are used to transport molecular material between cells.
The team developed a new antibody-based assay to capture from blood those exosomes that originate from nerve cells, and assessed their content of alpha-synuclein. In the largest study of its kind, they looked at 664 patients across the spectrum of Parkinson’s disease as well as diseases that mimic Parkinson’s but are associated with the accumulation of different proteins in the brain.
They found that patients at risk of developing Parkinson’s and those already exhibiting Parkinson’s symptoms had a twofold increase in the release of alpha-synuclein in exosomes, which remained high during the progression of the disease. Patients with Multiple System Atrophy (MSA), a disease that mimics Parkinson’s but is characterised by the accumulation of alpha-synuclein in glial rather than nerve cells in the brain, did not show a similar increase in alpha-synuclein in neuronal exosomes. This means that the blood test could be used to differentiate between two types of closely-related neurodegenerative diseases.
The researchers also found that simultaneous measurement of alpha-synuclein and another protein called clusterin significantly improved the diagnostic value of the test, making this assay the best blood-based test available for predicting specific Parkinson’s pathology versus neurodegenerative diseases characterised by other protein pathology.
The current study builds on previous discoveries by the team about how alpha-synuclein is handled and how this process can be disrupted in disease. Alexopolou et al (PNAS 2016) found that in healthy people the protein alpha-synuclein is targeted to specialised structures inside cells called endosomes, where it is normally sorted for destruction by lysosomes. Endosomes also release unwanted proteins outside the nerve cell in the vesicles called exosomes, especially when lysosomes go awry and are not able to carry out their normal destructive function. Dr Tofaris explains: “Because lysosomes do not function very efficiently in Parkinson’s disease, we hypothesised that a sensitive assay to isolate neuronal exosomes in blood could offer a mechanism-based biomarker. This is an example of how fundamental investigations in alpha-synuclein biology can be translated into a biomarker for clinical utility, in this case for the molecular stratification of parkinsonian syndromes.”