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Skin Α-Synuclein Deposits Differ in Clinical Variants Of www.nature.com/scientificreports OPEN Skin α-synuclein deposits difer in clinical variants of synucleinopathy: an in vivo study Received: 25 May 2018 V. Donadio 1, A. Incensi1, O. El-Agnaf2, G. Rizzo 1,3, N. Vaikath2, F. Del Sorbo4, Accepted: 29 August 2018 C. Scaglione1, S. Capellari 1,3, A. Elia4, M. Stanzani Maserati1, R. Pantieri1 & R. Liguori1,3 Published: xx xx xxxx 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 diferences 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-specifc for α-syn mature amyloid fbrils (syn-F1) were used. We found that p-syn showed the highest sensitivity and specifcity in disclosing skin α-syn deposits. In MSA abnormal deposits were only found in somatic fbers mainly at distal sites diferently from PAF, IPD and DLB displaying α-syn deposits in autonomic fbers mainly at proximal sites. PAF and DLB showed the highest p-syn load with a widespread involvement of autonomic skin nerve fbers. In conclusion: 1) p-syn in skin nerves was the optimal marker for the in vivo diagnosis of synucleinopathies; 2) the localization and load diferences of aggregates may help to identify specifc diagnostic traits and support a diferent pathogenesis among synucleinopathies. A common feature of synucleinopathies is the pathological accumulation of misfolded α-synuclein (α-syn) leading to neuron dysfunction and death1. Based on brain post-mortem studies diferent α-syn strains possi- bly expressing specifc molecular conformations have been proposed mainly in idiopathic Parkinson’s disease (IPD)2,3. In addition, a recent study demonstrated that α-syn strains extracted from the brain of Multiple System Atrophy (MSA) patients showed diferent prion properties than the strains extracted from the brain of IPD patients4. Tese fndings may suggest that distinct deposits of pathological α-syn are involved in neurodegen- erative diseases possibly providing the heterogeneity of synucleinopathies2,5 as described in prion disorders6. However, the pathogenetic mechanism underlying synucleinopathies is far from being fully understood because of the unavailability of a systematic study of α-syn aggregations in diferent clinical phenotypes and the lack of in vivo data allowing to analyse abnormal α-syn aggregates before the widespread difusion and the late maturation of these deposits7. Skin biopsy is a promising diagnostic tool for the in vivo diagnosis of synucleinopathies8–14 but a study simul- taneously testing diferent α-syn epitopes to detect abnormal deposits in all clinical variants of synucleinopathy is lacking. Hypothesizing the involvement of diferent α-syn deposits raises the possibility that a single marker could be unsuitable for disclosing abnormal deposits in all clinical variants. Tus a systematic study of α-syn deposits distribution in clinical variants of synucleinopathy is also needed for diagnostic purposes and to support skin biopsy as a promising diagnostic tool for these disorders. Tis study aimed to characterize abnormal α-syn deposits in skin nerves by immunofuorescence to ascertain the in vivo existence of diferent aggregates in variants of synucleinopathy. It may therefore contribute to clari- fying in synucleinopathies: 1) the optimal diagnostic marker to disclose skin nerves α-syn deposits in diferent variants; 2) whether an in vivo diferent distribution of α-syn deposits may justify the clinical variability. 1IRCCS Istituto delle Scienze Neurologiche, Bologna, Italy. 2Life Sciences Division, College of Science and Engineering, Hamad Bin Khalifa University (HBKU), Education City, Qatar Foundation, Doha, Qatar. 3Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy. 4Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy. Correspondence and requests for materials should be addressed to V.D. (email: vincenzo. [email protected]) SCIENTIFIC REPORTS | (2018) 8:14246 | DOI:10.1038/s41598-018-32588-8 1 www.nature.com/scientificreports/ IPD DLB PAF MSA Controls No. 15 12 5 12 10 Age Mean ± SD years 70 ± 3 75 ± 6 67 ± 10 66 ± 9 70 ± 3 Sex male:female 08:07 08:04 04:01 08:03 06:04 Dis. Dur. Mean ± SD years 6 ± 4 4 ± 2 7 ± 1 5 ± 1 — OH (%) 0 42 100 100 0 UPDRS 28 ± 8 11 ± 3 0 25 ± 3 (5°) 0 RBD (%) 15 80 0 82 0 Abnormal Cardiac MIBG (%) 100 (3) 100 (4) 100 0 (4) — Abnormal DatScan (%) 100 100 (10) 0 60 (7) — Brainstem abnormalities (MR) (%) 0 0 0 100 — Table 1. Clinical and laboratory fndings of patients. Dis.Dur. = disease duration; UPDRS-III = motor examination; OH = orthostatic hypotension; RBD = rem behavioral sleep disorder; the number in brackets represents the number of patients in whom the test was performed; °patients with MSA-P variant. Materials and Methods We studied 44 patients with synucleinopathy including 15 IPD patients fulflling established diagnostic criteria15, 12 patients who met the clinical diagnostic criteria for probable dementia with Lewy bodies (DLB-5 of them presenting with orthostatic hypotension)16, 5 fulflling 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 profles of the patients included in the study). Disease duration of recruited patients did not difer among diferent variants (p > 0.1). Recruited patients were well characterized since the clinical diagnosis was supported by abnormal laboratory tests showing cardiac postganglionic sympathetic denervation (123-I-MIBG)19, dopaminergic nigrostriatal abnor- malities (123I-iofupane-DatScan)20 or brainstem and cerebellum atrophy and/or the hot-cross bun sign (brain MR)21,22. Ten age-matched healthy subjects served as controls. Te procedures used were approved by the local Human Ethics Committee (Comito Etico Indipendente-AUSL Bologna, cod. 13004) and followed the Helsinki Declaration regarding international clinical research involving human beings. All participants gave their written informed consent to be included in the study. Skin biopsy. Following a previously described protocol11,23 3 mm punch biopsies were taken from proximal and distal hairy skin sites. Te proximal site included the cervical C7 paravertebral area whereas distal sites were located in the thigh (15 cm above the patella) and distal leg (10 cm above the lateral malleolus). Two samples were taken in each skin site 3–4 centimetres away11,23. According to previously published procedures15,24, skin samples were immediately fxed in cold Zamboni’s fxative and kept at 4 °C overnight. Skin sections were obtained using a freezing sliding microtome (HM550, Termo Scientifc, Walthan, MA, USA). Immunofluorescence characterization of skin nerve α-syn aggregates. Ten μm skin sections were double-immunostained overnight (unless diferently specifed) with a panel of primary antibodies against α-syn epitopes and the rabbit or mouse pan-neuronal marker protein gene product 9.5 (PGP). Te correspondence between α-syn markers and PGP helped to verify the intraneuronal α-syn staining excluding non-specifc dot-like staining ofen experienced in patients and controls inside membranes, sweat glands tubules or vessel endothe- lium11. A rule to identify abnormal α-syn aggregates was the co-localization of PGP and antibodies against abnor- mal α-syn epitopes expression of C-terminal post-translational modifcations or amyloid fbrils. Furthermore, diferent primary antibodies against normal or abnormal α-syn and ubiquitin were also double stained to char- acterize abnormal α-syn deposits. A triple combination of antibodies was not allowed because of only two dif- ferent species of antibodies available (i.e. rabbit or mouse). Primary antibodies used in this study (reported in Table 1-supplemental fle) included antibodies against the native form of α-syn (n-syn) or α-syn core (NAC) and against C-terminal α-syn epitopes involved in post-translational modifcations such as rabbit or mouse (immu- nostained for only 1 hour) phosphorylation α-syn at serine 129 (p-syn) and tyrosine 125 (pY-syn), nitration at tyr125–133 (nY-syn). Amyloid α-syn fbrils were characterized by using a non-commercial antibody (syn-F1)25, whereas advanced glycation end products (AGEs) residues that may be linked to abnormal α-syn deposits26 were disclosed by a specifc marker. Furthermore, a specifc mouse monoclonal antibody against full-length ubiquitin a.a. 1–76 (m-ub, 1:100, Santa Cruz, USA; cod. Sc-8017) was used to detect ubiquitin deposits ofen associated with α-syn fbrils27. We have tried an overnight incubation of primary antibodies25 but the fnal staining on skin sections was poor. In addition the fnal dilution of primary antibodies was established afer testing a large range of dilutions. A non-commercial antibody to detect oligomeric forms of α-syn (syn-O)25 was also tested but it was not systematically used in this study because preliminary experiments showed a frequent co-localization with NAC in skin nerves of controls and patients in all dilution used (1: 5000 and 1:10.000, data not shown). Sections were then washed and secondary antibodies were added for an incubation of one hour. As sec- ondary antibodies, an anti-mouse or rabbit Alexa Fluor(R) 488 and anti-rabbit or mouse Jackson cyanine dye SCIENTIFIC REPORTS | (2018) 8:14246 | DOI:10.1038/s41598-018-32588-8 2 www.nature.com/scientificreports/ Figure 1. Abnormal intraneural p-syn aggregates in non-synaptic and synaptic fbers. Examples of phosphorylated α-synuclein aggregates in a non-synaptic fber of a patient with MSA (A) and synaptic fbers of a DLB patient (B) disclosed by confocal microscope (x400).
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