A variable poly-T sequence modulates alpha-synuclein isoform expression and is associated with aging.
alpha-Synuclein, the main component of proteinaceous inclusions in synucleinopathies, is centrally involved in aggregation processes preceding Lewy body formation. Here we describe a new alpha-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 alpha-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 alpha-synuclein 126 expression levels, whereas the longest poly-T stretch (12T) was accompanied by the highest alpha-synuclein 126 expression levels. Thus, three different expression-level-specific genotypes, with 5T+ genotypes as low alpha-synuclein 126 expression genotypes and 12T+ genotypes as high alpha-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 alpha-synuclein 126 expression genotypes at ages under 60 years and high alpha-synuclein 126 expression genotypes at ages over 80 years. To determine human specificity of the variable poly-T strech, the mouse alpha-synuclein gene sequence was analyzed. Although alpha-synuclein is very well conserved in vertebrates, the poly-T sequence was found to be absent in mice, and an alpha-synuclein 126 mouse homologue could not be detected. In conclusion, this newly identified poly-T polymorphism is a human-specific sequence; its length influences alpha-synuclein 126 expression levels; and, finally, it seems to exert a specific influence on normal aging.
Beyer
Katrin
K
Department of Pathology, Hospital Germans Trias i Pujol, Autonomous University of Barcelona, Badalona, Spain. katrinbeyer@hotmail.com
Humbert
Jordi
J
Ferrer
Anna
A
Lao
José I
JI
Latorre
Pilar
P
Lopez
Dolores
D
Tolosa
Eduard
E
Ferrer
Isidro
I
Ariza
Aurelio
A
D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism*; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D016022:Case-Control Studies; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D008969:Molecular Sequence Data; D020033:Protein Isoforms; D012016:Reference Values; D017385:Sequence Homology; D013045:Species Specificity; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism
D020033:Protein Isoforms; D051844:alpha-Synuclein