The aggregation state of α-synuclein deposits in dermal nerve fibers of patients with Parkinson's disease resembles that in the brain

Introduction: Phosphorylated alpha-synuclein (p-alpha-syn) can be detected in dermal nerve fibers of patients with Parkinson's disease (PD) and multiple system atrophy (MSA). Here we investigated whether p-alpha-syn in the cutaneous nerve fibers represents misfolded aggregated protein. Methods: Using immunofluorescence with conformation specific antibodies and digestion with proteinase K (PK), we studied skin biopsies from a cohort of patients with early stage PD (Hoehn and Yahr I/II, n = 27), MSA with predominant parkinsonism (MSA-P, n = 8) and normal controls (n = 21). Results: We could show that a-synuclein (alpha-syn) found in the dermal nerve fibers in PD and MSA-P is not only phosphorylated but represents PK resistant and truncated aggregated protein. Comparison with a post mortem midbrain sample revealed a similar staining pattern of pathologic alpha-syn lesions in the PD brain. Conclusion: Immunostaining of nerve fibers with different conformation specific antibodies and digestion with PK gave comparable results between midbrain and skin sections, showing that cutaneous nerve deposits of alpha-syn are structurally similar to Lewy pathology in the brain and are highly specific for synucleinopathy.