INDEL Length and Haplotypes in the β-Synuclein Gene: A Key to Differentiate Dementia with Lewy Bodies?¹

Article type: Research Article

Authors: Gámez-Valero, Ana^{a; b} | Canet-Pons, Julia^{a; 2} | Urbizu, Aintzane^{a; 3} | Anillo, Ana^a | Santos, Cristina^c | Ariza, Aurelio^a | Beyer, Katrin^a

Affiliations: [a] Department of Pathology, Hospital Universitari and Health Sciences Research Institute Germans Trias i Pujol, Universitat Autònoma de Barcelona, Spain | [b] REMAR-IVECAT group, Health Sciences Research Institute Germans Trias i Pujol, Barcelona, Spain | [c] Unitat d’Antropologia Biològica, Departament de Biologia Animal, Biologia Vegetal i Ecologia, Universitat Autònoma de Barcelona, Spain

Correspondence: [*] Correspondence to: Katrin Beyer, PhD, Department of Pathology, Hospital Universitari Germans Trias i Pujol, Ctra de Canyet s/n, 08916 Badalona, Barcelona, Spain. Tel.: +34 93 497 88 53; E-mail: [email protected].

Note: [1] This article received a correction notice (Erratum) with the reference: 10.3233/JAD-219003, available at https://content.iospress.com/articles/journal-of-alzheimers-disease/jad219003.

Note: [2] Present address: Experimental Neurology Department, Goethe University Hospital, Frankfurt am Main, Germany

Note: [3] Present address: Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, USA

Abstract: Lewy body diseases (LBD) include Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) and together with Alzheimer’s disease (AD) they show an important neuropathological and clinical overlap. The human alpha- and beta-synuclein genes (SNCA and SNCB) are key factors for the development of Lewy body diseases. Here, we aimed to analyze the genotype distribution of potentially functional SNPs in SNCA and SNCB, perform haplotype analysis for SNCB, and to identify functional insertion and deletion (INDEL) variations within the regulatory region of SNCB which might be responsible for the drastically diminished beta-synuclein levels reported for pure DLB. Thus, we genotyped brain samples from AD, DLB, PD, and healthy controls for two SNCA and four SNCB SNPs. We also analyzed INDEL variations upstream of SNCB, determined SNCB expression levels, and correlated INDEL lengths with expression levels. Applying Fisher’s exact, chi-square, ANOVA tests, and the ΔΔCt method, we found disease-specific genotype distribution of SNCA and SNCB SNPs. Additionally, we identified three INDEL variations upstream of SNCB and showed that the INDEL allele lengths were associated with SNCB expression levels. INDEL alleles associated with low SNCB expression were accumulated in pure DLB. Finally, one major and four minor DLB specific SNCB haplotypes were identified with Haploview and Arlequin. In summary, our study showed that different SNCA and SNCB genotypes are associated with the development of either PD or DLB, and that the frequencies of genotypes associated with low SNCB expression are elevated in DLB.

Keywords: α-synuclein gene (SNCA), β-synuclein gene (SNCB), dementia with Lewy bodies, haplotypes, INDEL variations, Parkinson’s disease

DOI: 10.3233/JAD-180074

Journal: Journal of Alzheimer's Disease, vol. 65, no. 1, pp. 207-219, 2018