Quantitative measures of total and phosphorylated alpha-synuclein in skin tissue as potential biomarkers for synucleinopathies

BackgroundAlpha-synuclein can be detected in skin biopsies of individuals with synucleinopathies. However, quantitative data of total and phosphorylated Serine 129 (pS129) alpha-synuclein in skin biopsies are scarce.ObjectiveWe aimed to investigate the biomarker potential of quantitative total and pS129 alpha-synuclein measurements in skin biopsies from people with synucleinopathies and controls.MethodsWe developed and validated AlphaLISA™ immunoassays to determine total and pS129 alpha-synuclein concentrations. Postmortem skin biopsies of Parkinson's disease (PD: n = 18), Dementia with Lewy bodies (DLB: n = 3), Multiple System Atrophy (MSA: n = 5) and control (n = 5) subjects were collected at the cervical vertebra C7. Brain tissues (middle temporal gyrus and substantia nigra) were collected from these same cases. In addition, skin biopsies of controls (n = 20) and PD cases (n = 40) were obtained from the ProPark cohort.ResultsTotal and pSer129 alpha-synuclein could be robustly detected and quantified in all skin samples. We observed a trend towards increased total (+58%, p = 0.055) and pS129 (+131%, p = 0.060) alpha-synuclein skin concentrations in synucleinopathy cases compared to controls. We found no correlations between pS129 alpha-synuclein concentrations in paired brain and skin tissues from the same donors. pS129 alpha-synuclein concentrations were similar for clinical PD cases and controls and there was no correlation with motor symptom severity (UPDRS-III).ConclusionsThese findings highlight that total and pS129 alpha-synuclein can be biochemically quantified in skin biopsies, but warrant further validation and investigation to asses its potential as a diagnostic biomarker in clinical cohorts.