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

• Published in: Parkinsonism & related disorders 2023-10, Vol.115, p.105832-105832, Article 105832
• Main Authors: Arnaldo, Laura, Urbizu, Aintzane, Serradell, Mònica, Gaig, Carles, Anillo, Ana, Gea, Mireia, Vilas, Dolores, Ispierto, Lourdes, Muñoz-Lopetegi, Amaia, Mayà, Gerard, Pastor, Pau, Álvarez, Ramiro, Santamaria, Joan, Iranzo, Alex, Beyer, Katrin
• Format: Article
• Language: English
• Subjects: Dementia with Lewy bodies; GBA; Isolated REM sleep behavior disorder; Parkinson disease; Transcript variants; α-synuclein; α-synuclein gene SNCA
• ISSN: 1353-8020; 1873-5126
• DOI: 10.1016/j.parkreldis.2023.105832

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. 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. 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. 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. •SNCA transcript expression is reduced in blood in IRBD patients.•SNCAtv3 levels decrease with increased IRBD duration, especially in younger patients.•Rs356219-AA genotype frequency is increased in IRBD patients who developed PD and DLB.•Rs2736990-CC genotype frequency is increased in IRBD patients who remained disease-free over time.