Skin \u03b1-synuclein deposits differ in clinical variants of synucleinopathy: an in vivo study

V Donadio,R Pantieri,G Rizzo,M Stanzani Maserati,O El-Agnaf,S Capellari,C Scaglione,A Incensi,R Liguori,F Del Sorbo,N Vaikath,A Elia

doi:10.1038/s41598-018-32588-8

Abstract

We aimed to characterize in vivo α-synuclein (α-syn) aggregates in skin nerves to ascertain: 1) the optimal marker to identify them; 2) possible differences between synucleinopathies that may justify the clinical variability. We studied multiple skin nerve α-syn deposits in 44 patients with synucleinopathy: 15 idiopathic Parkinson’s disease (IPD), 12 dementia with Lewy Bodies (DLB), 5 pure autonomic failure (PAF) and 12 multiple system atrophy (MSA). Ten healthy subjects were used as controls. Antibodies against native α-syn, C-terminal α-syn epitopes such as phosphorylation at serine 129 (p-syn) and to conformation-specific for α-syn mature amyloid fibrils (syn-F1) were used. We found that p-syn showed the highest sensitivity and specificity in disclosing skin α-syn deposits. In MSA abnormal deposits were only found in somatic fibers mainly at distal sites differently from PAF, IPD and DLB displaying α-syn deposits in autonomic fibers mainly at proximal sites. PAF and DLB showed the highest p-syn load with a widespread involvement of autonomic skin nerve fibers. In conclusion: 1) p-syn in skin nerves was the optimal marker for the in vivo diagnosis of synucleinopathies; 2) the localization and load differences of aggregates may help to identify specific diagnostic traits and support a different pathogenesis among synucleinopathies.

Highlights

We aimed to characterize in vivo α-synuclein (α-syn) aggregates in skin nerves to ascertain: 1) the optimal marker to identify them; 2) possible differences between synucleinopathies that may justify the clinical variability
We studied 44 patients with synucleinopathy including 15 idiopathic Parkinson’s disease (IPD) patients fulfilling established diagnostic criteria[15, 12] patients who met the clinical diagnostic criteria for probable dementia with Lewy bodies (DLB-5 of them presenting with orthostatic hypotension)[16, 5] fulfilling diagnostic criteria for pure autonomic failure (PAF)[17] and 12 for MSA (5 MSA-P and 7 MSA-C)[18] (Table 1 reports demographic data and the clinical profiles of the patients included in the study)
The main results of our study were: 1) p-syn as the most sensitive and specific marker of abnormal α-syn deposits in skin nerves for the in vivo diagnosis of synucleinopathies; 2) different coexistent fibrillar and non-fibrillar α-syn deposits were found in clinical variants of synucleinopathy; 3) MSA displayed a peculiar pattern of abnormal deposits only found in somatosensory skin fibers and PAF-DLB showed the highest load of deposits with a widespread involvement of autonomic annexes

Summary

Introduction

We aimed to characterize in vivo α-synuclein (α-syn) aggregates in skin nerves to ascertain: 1) the optimal marker to identify them; 2) possible differences between synucleinopathies that may justify the clinical variability. Atrophy (MSA) patients showed different prion properties than the strains extracted from the brain of IPD patients[4] These findings may suggest that distinct deposits of pathological α-syn are involved in neurodegenerative diseases possibly providing the heterogeneity of synucleinopathies[2,5] as described in prion disorders[6]. It may contribute to clarifying in synucleinopathies: 1) the optimal diagnostic marker to disclose skin nerves α-syn deposits in different variants; 2) whether an in vivo different distribution of α-syn deposits may justify the clinical variability

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Conclusion