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Parkinson’s disease (PD) has a prevalence of 100-200/100000 and is one of the most common neurodegenerative diseases. It typically manifests with resting tremor, bradykinesia, rigidity and postural instability. The clinical symptoms correlate to specific histopathological alterations like the neuronal degeneration of dopaminergic neurons of Substantia nigra pars compacta and the appearance of intracytoplasmatic amyloidal inclusions, called Lewy bodies, in surviving cells. Lewy bodies primarily consist of fibrillated α-Synuclein, a neuronal presynaptic protein. The amyloid building property of α-Synuclein is thought to play an important role in the pathogenesis of PD and other synucleinopathies. There is mounting evidence that α-Synuclein oligomers, intermediate products of the mature fibrils of α-Synuclein, carry the actual cell toxic potential. Recently, the existence of naturally occurring polyclonal autoantibodies against α-Synuclein in serum of PD patients and healthy controls has been shown. They seem to take part in the metabolisation of α-Synuclein and display a neuroprotective effect in vitro. The clinical diagnosis of PD is challenged by the overlap of symptoms with other neurological diseases. Despite considerable scientific research, reliable biomarkers for the diagnosis of PD in common clinical practice are still missing. With upcoming neuroprotective therapies biomarkers are urgently needed, which correlate to the extent of neuronal degeneration. This study evaluated the natural occurring autoantibodies against α-Synuclein as potential biomarkers in PD. Therefore, an indirect ELISA was established and validated according to common clinical and laboratory standards in order to quantify the amount of the autoantibody in the human serum. Using affinity chromatography natural occurring autoantibodies were isolated from human intravenous immunoglobulin (IVIg) solutions. Binding specificity of purified IVIg autoantibodies was tested using Western-Blot, before they were applied in ELISA as standard and reference samples. Various blocking agents were tested for reducing unspecific binding of serum in the indirect ELISA. The established ELISA showed a specific decline in linearity-of-dilution experiments with an error rate less than 20%, an average spike-recovery of 91% and an intra- and inter-assay coefficient of variation of 3,7 and 8,8%, respectively. Patients with PD (n=63), with Alzheimer’s disease (AD) (n=43) and healthy controls (n=46) were recruited. Beside the age at study, duration and severity of disease (Hoehn and Yahr; UPDRS) was additionally assed in PD patients. In all cases levels of natural autoantobodies were measured. In several cases a previously published ELISA was used to additionally measure the amount of free α-Synuclein in serum. A statistical significant difference of the amount of autoantibodes was shown between healthy controls, patients with PD and patients with AD (p=0.005; Kruskal-Wallis test). Post-hoc multiple comparison of the groups with Dunn’s method revealed a significant difference between healthy controls vs. PD patients (p<0.05), AD vs. PD patients (p<0.05) und no difference between healthy controls vs. AD patients. No correlation was found between age at study, duration or severity of disease and the amount of free α-Synuclein with naturally occurring autoantibodies. Receiver Operating Characteristic (ROC) analysis was used to evaluate the diagnostic sensitivity and specificity of the assay. The area under the ROC curve (AUC: area under curve) was 0.662 (95% confidence interval: 0.561-0.763; p<0.05) for PD patients vs. healthy controls 0.650 (95% confidence interval: 0.545-0.754; p<0.05) for PD vs. AD patients. The Youden index revealed for PD patients vs. healthy controls a sensitivity and specificity of 32% and 98% and for PD vs. AD patients a sensitivity and specificity of 30% and 95%. With a fixed sensitivity of 85% a specificity of 25% for both comparisons was reached. The amount of free α-Synuclein did not differ between groups. This study showed for the first time significantly reduced levels of the naturally occurring autoantibody against α-Synuclein in the serum of PD patients compared to healthy controls and patients with AD. The established assay showed a moderate accuracy as a diagnostic tool in properly differentiating diagnostic groups. Further studies are necessary to assess the value of naturally occurring autoantibodies against α-Synuclein as a reliable biomarker for PD.