Synuclein-One study: skin biopsy detection of phosphorylated α-synuclein for diagnosis of synucleinopathies

Abstract

Finding an easily accessible and reliable tool to diagnose the diseases collectively defined as 'synucleinopathies' is an urgent, unmet priority. The synucleinopathies include Parkinson's disease, multiple system atrophy, pure autonomic failure and dementia with Lewy bodies. There are millions of people who have a diagnosis of a synucleinopathy, with more diagnosed every year. With accessibility, ease of implementation, consistently high sensitivity (>80%) and specificity approaching 100%, skin biopsy has great potential as the clinical test of choice for the diagnosis of synucleinopathies. The large, multi-center Synuclein-One study will determine the sensitivity, specificity, accuracy and precision of α-synuclein detection within punch skin biopsies in patients with clinically established synucleinopathies using standardized, robust methods suitable for large-scale analysis. Clinical Trial Registration: NCT04700722 (ClinicalTrials.gov).

Keywords: Parkinson's disease; phosphorylated α-synuclein; skin biopsy; synucleinopathy.

Conflict of interest statement

Financial & competing interests disclosure

The study is supported by NIH 5R44NS117214. CH Gibbons has received research support from Grifols, serves as a scientific advisor for CND Life Sciences and holds stock options in CND Life Sciences. R Freeman has served as a scientific advisor or received research support from Akcea, Biogen, CND Life Sciences and Vertex and holds stock options in CND Life Sciences. B Bellaire is employed by CND Life Sciences. T Levine has served as a scientific advisor for Grifols and FFF Enterprises and holds stock options in Corinthian Reference Lab and CND Life Sciences. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Figures

Figure 1.. Skin biopsy protocol.

In (A), three skin biopsies are taken from the distal leg, distal thigh and posterior cervical region using a 3 mm punch biopsy tool (B). The punch biopsy is sectioned into 50 μm sections (C). As shown in (D), the tissue sections are dual immunostained by protein gene product 9.5 (PGP 9.5), a pan-axonal marker, and by phosphorylated α-synuclein (P-SYN). The primary antibodies are labeled with immunofluorescent markers Cy3 and Cy5. The tissue is then viewed by confocal microscopy to identify nerve fibers stained by PGP 9.5 (E) by P-SYN (F) and the merged image (G) is used to confirm the presence of intra-axonal P-SYN.

Figure 2.. Study outline for clinical and pathological analysis of data.

Data flow through the course of the study. BIDMC: Beth Israel Deaconess Medical Center.