Pathophysiological Significance of α-Synuclein in Sympathetic Nerves: In Vivo Observations.

Background And Objectives: Lewy body diseases (LBDs) such as Parkinson disease (PD) feature increased deposition of α-synuclein (α-syn) in cutaneous sympathetic noradrenergic nerves. The pathophysiologic significance of sympathetic intraneuronal α-syn is unclear. We reviewed data about immunoreactive α-syn, tyrosine hydroxylase (TH, a marker of catecholaminergic fibers), and the sympathetic neurotransmitter norepinephrine (NE) in skin biopsies from control participants and patients with PD, the related LBD pure autonomic failure (PAF), the non-LBD synucleinopathy multiple system atrophy (MSA), or neurologic postacute sequelae of severe acute respiratory syndrome coronavirus 2 (neuro-PASC).

Methods: In a retrospective observational study, we reviewed data about α-syn-TH colocalization indexes and immunoreactive α-syn and TH signal intensities in arrector pili muscles, blood vessels, and sweat glands from neck skin biopsies and NE concentrations in simultaneously obtained thigh skin biopsies from participants studied at the NIH Clinical Center. LBD, MSA, and control group data were assessed by analyses of variance with the Tukey post hoc test for multiple comparisons. Similar analyses were performed for patients with PD or neuro-PASC vs control.

Results: Dermal α-syn-TH colocalization indexes and α-syn signal intensities from neck skin biopsies were examined in 18 controls (mean age 58 years, 50% female) and 53 LBD (66, 34%), 15 MSA (61, 33%), and 11 neuro-PASC (52, 82%) patients. The LBD group had higher α-syn-TH colocalization indexes than the controls (mean difference = 1.495, 95% CI 1.081-1.909, < 0.0001) and increased α-syn signal intensities in all 3 skin constituents (arrector pili: mean difference = 2.743, 95% CI 1.608-3.879, < 0.0001; blood vessels: mean difference = 2.157, 95% CI 1.095-3.219, < 0.0001; sweat glands: mean difference = 4.136, 95% CI 1.704-6.567, < 0.0001). The groups did not differ in either immunoreactive TH or NE. The neuro-PASC and PD groups had elevated α-syn-TH colocalization indexes compared with the controls, also with no group differences in immunoreactive TH or NE contents.

Discussion: LBDs and neuro-PASC entail increased α-syn-TH colocalization indexes in skin biopsies, without evidence of local denervation or noradrenergic deficiency. The results fail to support toxicity of intraneuronal α-syn in cutaneous sympathetic noradrenergic nerves in either LBDs or neuro-PASC. The neuro-PASC data raise the possibility of sympathetic intraneuronal α-syn deposition as part of postinfectious immune or inflammatory processes.