Phosphorylated α-Synuclein Deposits in Cutaneous Nerves of Early Parkinsonism

The role of peripheral phosphorylated-α-Synuclein (p-α-syn) deposition on nerve degeneration in synucleinopathies is still unknown.To assess the cutaneous neural distribution of p-α-Syn deposits and its correlation with clinical data and with morphology and function of cutaneous sensory and autonomic nerves in early Parkinson's disease (PD) and multiple system atrophy-parkinson type (MSA-p).We recruited 57 PD (F/M = 21/36; age 63.5±9.4 years) and 43 MSA-p (F/M = 16/27; age 62.3±9.0 years) patients within 2 years from motor symptoms. We applied questionnaires and clinical scales, sensory thresholds, and sudomotor testing to assess severity of motor and non-motor involvement and sensory and autonomic dysfunction. We quantified, in skin biopsy from thigh, leg, and fingertip, epidermal, pilomotor, and sudomotor nerve fibers, Meissner corpuscles and intrapapillary myelinated endings and the neural distribution of p-α-syn deposits.Compared to controls, we found a cutaneous denervation paralleling functional and clinical impairment. Sensory and autonomic denervation was more severe in MSA-p than in PD. Deposits of p-α-syn were found in the majority of patients, with no significant differences among sites in both groups. Higher occurrence of p-α-syn deposits in autonomic nerves differentiated (p < 0.01) PD from MSA-p. p-α-syn deposits correlated positively with sudomotor function, epidermal, pilomotor and sudomotor nerve densities, and inversely with non-motor symptoms and disease progression.Our work demonstrated an early peripheral sensory and autonomic involvement in synucleinopathies, more severe in MSA-p than in PD. Higher p-α-syn deposits in autonomic nerves differentiated PD from MSA-p. p-α-syn deposits were associated with preserved innervation and slower disease progression.