Allelic imbalance of expression and epigenetic regulation within the alpha-synuclein wt and c.209G>A gene alleles in Parkinson Disease

Gerassimos E. Voutsinas (1) , Eleana F. Stavrou (2) , Gerassimos Karousos (2) , Aggeliki Dasoula (3) , Adamantia Papachatzopoulou (2) , Maria Syrrou (2) , Annemieke Verkerk (4) , Peter van Der Spek (2) , George Patrinos (5) , Reinhard Stoger (6) , Aglaia Athanassiadou (2)

1 Laboratory of Environmental Mutagenesis and Carcinogenesis
2 Dept of Biology
3 Laboratory of General Biology
4 Dept of Bioinformatics
5 Dept of Pharmacy
6 Dept of Biology

ABSTRACT Genetic alterations in the alpha-synuclein (SNCA) gene have been implicated in Parkinson Disease (PD), including point mutations, gene multiplications and sequence variations within the promoter. Such alterations may be involved in pathology through structural changes or overexpression of the protein leading to protein aggregation, as well as through impaired gene expression. It is, therefore, of importance to specify the parameters that regulate SNCA expression in its normal and mutated state. We studied the expression of SNCA alleles in a lymphoblastoid cell line and in the blood cells of a patient heterozygous for p.Ala53Thr, the first mutation to be implicated in PD pathogenesis. Here, we provide evidence that: (1) SNCA shows monoallelic expression in this patient; (2) epigenetic silencing of the mutated allele involves histone modifications but not DNA methylation; and (3) steady state mRNA levels deriving from the normal SNCA allele in this patient exceed those of the two normal SNCA alleles combined, in matching, control individuals. An imbalanced SNCA expression in this patient is thus documented, with silencing of the p.Ala53Thr allele and up-regulation of the wt-allele. This phenomenon is demonstrated for a first time in the SNCA gene and may have important implications for PD pathogenesis.

Mots clés: Life Sciences

Gerassimos E. Voutsinas, Eleana F. Stavrou, Gerassimos Karousos, Aggeliki Dasoula, Adamantia Papachatzopoulou, et al.. Allelic imbalance of expression and epigenetic regulation within the alpha-synuclein wt and c.209G>A gene alleles in Parkinson Disease. Human Mutation, 2010, 31 (6), pp.685. ⟨10.1002/humu.21248⟩. ⟨hal-00552376⟩