The deposition of alpha-synuclein in the brain, the neuropathological hallmark of Parkinson’s disease (PD), follows a distinct anatomical and temporal sequence. This study aimed to characterize alpha-synuclein deposition in cutaneous nerves from patients with PD. We further strived to explore whether peripheral nerve involvement is intrinsic to PD and reflective of known features of brain pathology, which could render it a useful tool for pathogenetic studies and pre-mortem histological diagnosis of PD. We obtained skin biopsies from the distal and proximal leg, back and finger of 31 PD patients and 35 controls and quantified the colocalization of phosphorylated alpha-synuclein in somatosensory and autonomic nerve fibers and the pattern of loss of different subtypes of dermal fibers. Deposits of phosphorylated alpha-synuclein were identified in 16/31 PD patients but in 0/35 controls (p < 0.0001). Quantification of nerve fibers revealed two types of peripheral neurodegeneration in PD: (1) a length-dependent reduction of intraepidermal small nerve fibers (p < 0.05) and (2) a severe non-length-dependent reduction of substance P-immunoreactive intraepidermal nerve fibers (p < 0.0001). The latter coincided with a more pronounced proximal manifestation of alpha-synuclein pathology in the skin. The histological changes did not correlate with markers of levodopa toxicity such as vitamin B12 deficiency. Our findings suggest that loss of peripheral nerve fibers is an intrinsic feature of PD and that peripheral nerve changes may reflect the two types of central alpha-synuclein-related PD pathology, namely neuronal death and axonal degeneration. Detection of phosphorylated alpha-synuclein in dermal nerve fibers might be a useful diagnostic test for PD with high specificity but low sensitivity.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-014-1284-0) contains supplementary material, which is available to authorized users.

Background MSA is characterized by deposition of alpha‐synuclein (α‐Syn) in oligodendrocytes and central nervous system (CNS) neurons. After recently detecting phospho‐α‐Syn (p‐α‐Syn) in dermal nerve fibers of patients with Parkinson's disease (PD), we assessed skin biopsies from patients with MSA to evaluate its potential role as a biomarker. Methods Skin biopsies of patients with MSA (n = 12), idiopathic PD (n = 30), tauopathies (n = 15), and normal controls (n = 39) were analyzed. P‐α‐Syn within dermal nerves was detected by immunofluorescence staining. Results p‐α‐Syn was found in 67% of patients with MSA and Parkinson's disease, but not in patients with tauopathy or controls when analyzing 15 consecutive sections. Sensitivity could be increased to 75% and 73%, respectively, by analyzing serial sections. In contrast to PD, where p‐α‐Syn clustered in autonomic fibers, deposits were mainly found in unmyelinated somatosensory fibers in MSA. Conclusion α‐Syn pathology in MSA is not restricted to the CNS, and skin biopsy may be useful for the premortem study of p‐α‐Syn. © 2015 International Parkinson and Movement Disorder Society

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