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Parkinson’s disease is closely associated with abnormal forms of a protein called alpha-synuclein, or α-Syn. As the disease develops, misfolded and aggregated forms of this protein accumulate in the nervous system.
Because α-Syn can also be measured in blood, researchers have explored whether it could serve as a biomarker for Parkinson’s disease. The problem is that large amounts of α-Syn in blood come from red blood cells, making it difficult to isolate the smaller signal originating from the nervous system.
Researchers at King Abdullah University of Science and Technology (KAUST) have developed an electronic assay designed to measure disease-related forms of α-Syn carried by neuronal extracellular vesicles in blood.
Using extracellular vesicles to find a brain-derived signal
Extracellular vesicles, or EVs, are tiny membrane-bound particles released by cells. They carry proteins, RNA and other molecules from their cells of origin, allowing them to transfer biological information between cells.
Some extracellular vesicles circulating in the bloodstream originate from neurons. These neuronal EVs can contain molecules related to activity and disease processes in the brain.
That makes them an attractive source of biomarkers for neurological diseases. By enriching for neuronal extracellular vesicles, researchers may be able to reduce interference from proteins originating elsewhere in the body.
In Parkinson’s disease, this is particularly important because most α-Syn measured directly in blood comes from peripheral sources such as red blood cells.
Multiplexed electronic detection of α-Syn proteoforms in neuronal EVs for PD diagnosis
(A) Misfolded α-Syn originating from degenerating neurons is released into circulation within neuronal EVs. These EVs carry total, aggregated, and pSer129 α-Syn proteoforms that reflect underlying brain pathology. (B) OECT sensor configuration used for multiplex detection. The device consists of patterned p-type organic mixed ionic-electronic conductor p(g3C2T2-T) (width, 100 μm; length, 10 μm), and functionalized gate electrodes bearing capture antibodies for total α-Syn, aggregated α-Syn, and pSer129 α-Syn. (C) Clinical workflow: serum is collected from participants, neuronal EVs are isolated via L1CAM enrichment and lysed, and α-Syn proteoforms are quantified by the OECT assay. Combined proteoform signatures are analyzed using a neural network classifier to differentiate healthy controls (HC), individuals with isolated iRBD (i.e., prodromal PD), and clinically diagnosed PD.
Measuring several forms of alpha-synuclein
The researchers developed a biosensor based on an organic electrochemical transistor. The system was designed to analyze L1CAM-positive extracellular vesicles isolated from serum and measure three forms of α-Syn at the same time.
These included total α-Syn, aggregated α-Syn and α-Syn phosphorylated at serine 129.
Serine-129 phosphorylation is commonly associated with abnormal α-Syn found in Parkinson’s disease pathology, while aggregated α-Syn reflects the tendency of the protein to form larger abnormal structures.
Measuring several forms together may provide more information than measuring total α-Syn alone.
Detecting extremely small amounts of protein
One challenge in working with neuronal extracellular vesicles is that they are present at very low concentrations in blood.
The electronic platform achieved detection in the low femtomolar range, allowing the researchers to measure very small amounts of α-Syn associated with the isolated EVs.
The assay was then evaluated in serum samples from 66 individuals, including people with clinically diagnosed Parkinson’s disease, individuals at prodromal stages and controls.
When the three α-Syn measurements were combined, the assay distinguished Parkinson’s disease from controls with 90.9 percent accuracy in this cohort, with 88.6 percent sensitivity and 90.9 percent specificity.
Potential for earlier detection
Parkinson’s disease can begin developing years before its characteristic movement symptoms become obvious. This creates interest in biomarkers that could identify disease-related biological changes earlier.
Neuronal extracellular vesicles may provide a useful window into these early changes because they carry molecular material originating from nervous system cells.
An assay that can measure multiple disease-associated α-Syn forms from a blood sample could potentially support less invasive approaches to Parkinson’s disease detection and monitoring.
However, the results come from a relatively small clinical cohort. Larger and more diverse studies will be needed to determine how well the approach performs across broader patient populations and whether it can reliably identify individuals before clear clinical symptoms appear.
Extracellular vesicles as neurological biomarkers
The findings demonstrate how extracellular vesicles can help researchers focus on biologically relevant molecules that would otherwise be difficult to distinguish in blood.
Rather than measuring all circulating α-Syn together, the researchers used neuronal EVs to enrich for signals more closely connected to the nervous system.
This approach could contribute to the broader development of liquid biopsy strategies for neurological disease, in which extracellular vesicles provide access to molecular information from tissues that are difficult to sample directly.
