A variable poly-T sequence modulates α-synuclein isoform expression and is associated with aging

Katrin Beyer, Jordi Humbert, Anna Ferrer, José I. Lao, Pilar Latorre, Dolores Lopez, Eduard Tolosa, Isidro Ferrer, Aurelio Ariza

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16 Citations (Scopus)

Abstract

α-Synuclein, the main component of proteinaceous inclusions in synucleinopathies, is centrally involved in aggregation processes preceding Lewy body formation. Here we describe a new α-synuclein gene poly-T polymorphism that is situated upstream to exon 3 and consists of three different alleles. A correlation between poly-T length and expression of α-synuclein 126 mRNA, an isoform lacking exon 3, was detected in the human cerebral cortex. Specifically, when compared with the most frequent 7T/7T genotype, the shortest poly-T stretch (5T) was associated with the lowest α-synuclein 126 expression levels, whereas the longest poly-T stretch (12T) was accompanied by the highest α-synuclein 126 expression levels. Thus, three different expression-level-specific genotypes, with 5T+ genotypes as low α-synuclein 126 expression genotypes and 12T+- genotypes as high α-synuclein 126 expression genotypes, could be established. Poly-T genotype distributions were also analyzed in a healthy control population. Age-dependent variations in this distribution were observed and showed accumulation of low α-synuclein 126 expression genotypes at ages under 60 years and high α-synuclein 126 expression genotypes at ages over 80 years. To determine human specificity of the variable poly-T strech, the mouse α-synuclein gene sequence was analyzed. Although α-synuclein is very well conserved in vertebrates, the poly-T sequence was found to be absent in mice, and an α-synuclein 126 mouse homologue could not be detected. In conclusion, this newly identified poly-T polymorphism is a human-specific sequence; its length influences α-synuclein 126 expression levels; and, finally, if seems to exert a specific influence on normal aging. © 2007 Wiley-Liss, Inc.
Original languageEnglish
Pages (from-to)1538-1546
JournalJournal of Neuroscience Research
Volume85
Issue number7
DOIs
Publication statusPublished - 15 May 2007

Keywords

  • α-synuclein 126
  • α-synuclein polymorphism
  • Differential isoform expression
  • Mouse α-synuclein 126

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