Peripheral α-synuclein isoforms are potential biomarkers for diagnosis and prognosis of isolated REM sleep behavior disorder

Laura Arnaldo; Aintzane Urbizu; Mònica Serradell; Carles Gaig; Ana Anillo; Mireia Gea; Dolores Vilas; Lourdes Ispierto; Amaia Muñoz-Lopetegi; Gerard Mayà; Pau Pastor; Ramiro Álvarez; Joan Santamaria; Alex Iranzo; Katrin Beyer

doi:10.1016/j.parkreldis.2023.105832

Peripheral α-synuclein isoforms are potential biomarkers for diagnosis and prognosis of isolated REM sleep behavior disorder

Parkinsonism Relat Disord. 2023 Oct:115:105832. doi: 10.1016/j.parkreldis.2023.105832. Epub 2023 Sep 3.

Authors

Affiliations

¹ Department of Pathology, Hospital Universitari and Health Sciences Research Institute Germans Trias i Pujol, Badalona, Spain; Universitat Autònoma de Barcelona, Barcelona, Spain.
² Department of Pathology, Hospital Universitari and Health Sciences Research Institute Germans Trias i Pujol, Badalona, Spain.
³ IDIBAPS, CIBERNED, Neurology Service, Sleep Disorders Center, Hospital Clínic de Barcelona, Barcelona, Spain.
⁴ Unit of Neurodegenerative Diseases, Department of Neurology, University Hospital Germans Trias i Pujol and the Germans Trias I Pujol Research Institute (IGTP) Badalona, Barcelona, Spain.
⁵ IDIBAPS, CIBERNED, Neurology Service, Sleep Disorders Center, Hospital Clínic de Barcelona, Barcelona, Spain. Electronic address: airanzo@clinic.cat.
⁶ Department of Pathology, Hospital Universitari and Health Sciences Research Institute Germans Trias i Pujol, Badalona, Spain; Universitat Autònoma de Barcelona, Barcelona, Spain. Electronic address: kbeyer@igtp.cat.

PMID: 37678102
DOI: 10.1016/j.parkreldis.2023.105832

Abstract

Introduction: Isolated REM sleep behavior disorder (IRBD) represents an early manifestation of the synucleinopathies Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Aggregation of abnormal α-synuclein and its increased expression in the brain is crucial in the development of the synucleinopathies. Whereas α-synuclein gene (SNCA) transcripts are overexpressed in brain, a concomitant reduction occurs in blood of DLB patients. We assessed whether this decrease is also detectable in IRBD.

Methods: 108 IRBD patients and 149 controls were included of which 29 IRBD and 32 control cases were available for expression studies. Expression of SNCAtv1, SNCAtv2, SNCAtv3 and SNCA126 isoforms, and GBA were determined by real-time PCR. Genotype distribution of SNCA SNPs, rs356219 and rs2736990, and correlation with SNCA expression was analyzed.

Results: Expression of all SNCA transcripts was reduced in IRBD blood whereas GBA expression did not change. SNCAtv3 expression correlated inversely with IRBD duration, being lower in patients with longer follow-up. Rs356219-AA genotype frequency was increased in IRBD patients who later developed PD and DLB. Rs2736990-CC frequency was increased among IRBD cases who remained disease-free. No correlation was observed between rs356219 and rs2736990 genotypes and SNCA transcript levels.

Conclusion: SNCA transcript expression is decreased in blood in IRBD, and levels decrease with IRBD duration. Our findings indicate that changes in SNCA expression occur in the earliest stages of the synucleinopathies before motor and cognitive symptoms become apparent.

Keywords: Dementia with Lewy bodies; GBA; Isolated REM sleep behavior disorder; Parkinson disease; Transcript variants; α-synuclein; α-synuclein gene SNCA.