Alpha-synuclein is increased in erythrocytes in Parkinson’s Disease cases

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Abstract Idiopathic Parkinson’s disease (iPD) is the second most common neurodegenerative disease after Alzheimer’s disease (AD). Mutations in the SCNA gene, which encodes the protein alpha synuclein (α-syn), are associated with familial forms of Parkinson's disease (PD). Additionally, Lewy bodies (LBs) rich in α-synuclein are a hallmark of idiopathic Parkinson's disease (iPD) pathology. Unlike AD, there are no effective blood-based diagnostic assays for iPD. Recent studies show that measures of misfolded α-syn in cerebrospinal fluid (CSF) and skin biopsies reflect the diagnosis of iPD. The presence of misfolded α-syn suggests that the altered cellular processes in the brain that lead to aggregated α-syn may also occur in the periphery. However, CSF and skin biopsies are intrusive, highlighting the need for a blood-based diagnostic assay. Erythrocytes are the richest source of α-syn in the body, and we hypothesized that peripheral α-syn changes could be detected in erythrocytes in iPD. To test this hypothesis, we used a targeted liquid chromatography-mass spectrometry (LC-MS) assay, that included 15N-enriched recombinant α-syn as an internal standard. We compared the levels of α-syn in erythrocytes from iPD patients, AD patients, and healthy controls (CN). α-syn concentrations were significantly elevated in iPD (48.1 (29.7) µg*mL-1 of erythrocytes, median (IQR)) compared to CN (36.1 (28.4) µg*mL-1) and no difference was observed in AD (33.5 (18.1) µg*mL-1). Although α-syn levels were significantly elevated in iPD, the receiver operating characteristic (ROC) analysis yielded an area under the curve (AUC) of 0.62, indicating that erythrocytic α-syn levels alone are not sufficient for diagnostic purposes.

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