MAPT expression and splicing is differentially regulated by brain region: relation to genotype and implication for tauopathies.
The MAPT (microtubule-associated protein tau) locus is one of the most remarkable in neurogenetics due not only to its involvement in multiple neurodegenerative disorders, including progressive supranuclear palsy, corticobasal degeneration, Parksinson's disease and possibly Alzheimer's disease, but also due its genetic evolution and complex alternative splicing features which are, to some extent, linked and so all the more intriguing. Therefore, obtaining robust information regarding the expression, splicing and genetic regulation of this gene within the human brain is of immense importance. In this study, we used 2011 brain samples originating from 439 individuals to provide the most reliable and coherent information on the regional expression, splicing and regulation of MAPT available to date. We found significant regional variation in mRNA expression and splicing of MAPT within the human brain. Furthermore, at the gene level, the regional distribution of mRNA expression and total tau protein expression levels were largely in agreement, appearing to be highly correlated. Finally and most importantly, we show that while the reported H1/H2 association with gene level expression is likely to be due to a technical artefact, this polymorphism is associated with the expression of exon 3-containing isoforms in human brain. These findings would suggest that contrary to the prevailing view, genetic risk factors for neurodegenerative diseases at the MAPT locus are likely to operate by changing mRNA splicing in different brain regions, as opposed to the overall expression of the MAPT gene.
Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
Daniah
D
Trabzuni
Selina
S
Wray
Jana
J
Vandrovcova
Adaikalavan
A
Ramasamy
Robert
R
Walker
Colin
C
Smith
Connie
C
Luk
J Raphael
JR
Gibbs
Allissa
A
Dillman
Dena G
DG
Hernandez
Sampath
S
Arepalli
Andrew B
AB
Singleton
Mark R
MR
Cookson
Alan M
AM
Pittman
Rohan
R
de Silva
Michael E
ME
Weale
John
J
Hardy
Mina
M
Ryten
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism*; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D054643:INDEL Mutation; D008297:Male; D008875:Middle Aged; D009928:Organ Specificity; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D040641:Quantitative Trait Loci; D022821:RNA Splice Sites; D024801:Tauopathies / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D055815:Young Adult; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
C054369:MAPT protein, human; D020033:Protein Isoforms; D022821:RNA Splice Sites; D016875:tau Proteins