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Cited by 252Alzheimer's disease research and treatmentsRNA Research and SplicingAmyotrophic Lateral Sclerosis Research

MAPT expression and splicing is differentially regulated by brain region: relation to genotype and implication for tauopathies

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Trabzuni, Daniah, Wray, Selina, Vandrovcova, Jana, Ramasamy, Adaikalavan, Walker, Robert, Smith, Colin, Luk, Connie, Gibbs, J. Raphael +10 more·2012·Human Molecular Genetics
DOI 10.1093/hmg/dds238PMC PMC3428157
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Abstract

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.

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  • MAPT expression was elevated selectively within the neocortex, with highest total MAPT RNA levels in the temporal lobe.

    “Building on prior studies evaluating MAPT expression within the normal adult brain [31], we found elevated total MAPT expression selectively within the neocortex. Across all evaluated regions, total MAPT RNA levels were highest within the temporal lobe, one of the earliest regions implicated in FTD ([4], see Figure 5).”

    From Shared genetic risk between corticobasal degeneration, progressive supranuclear palsy, and frontotemporal dementia (2017) · cites this paper as [31]

  • In humans, tau mRNA expression and protein levels in the brain can vary greatly.

    “In humans, tau mRNA expression and protein levels in the brain can vary greatly (Trabzuni et al., 2012).”

    From Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms (2022) · cites this paper as Trabzuni et al., 2012

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Authors
Trabzuni, D., Wray, S., Vandrovcova, J., Ramasamy, A., Walker, R., Smith, C., Luk, C., Gibbs, J. R., Dillman, A., Hernandez, D. G., Arepalli, S., Singleton, A. B., Cookson, M. R., Pittman, A. M., de Silva, R., Weale, M. E., Hardy, J., & Ryten, M.
Affiliations
  • King Faisal Specialist Hospital & Research Centre (SA)
  • National Hospital for Neurology and Neurosurgery (GB)
  • Guy's Hospital (GB)
  • University of Edinburgh (GB)
  • National Institutes of Health (US)
Corresponding author
Ryten, Mina
ORCID
Venue
Human Molecular Genetics
Publisher
Oxford University Press (OUP)
Published
2012-06-20
Volume
21
Issue
18
Pages
4094-4103
ISSN
  • 0964-6906 (ISSN-L)
  • 1460-2083
DOI
10.1093/hmg/dds238
PMC
PMC3428157
OpenAlex
W2106158921
Cited by
252
References
7
Citations by year
2026: 10 · 2025: 18 · 2024: 23 · 2023: 40 · 2022: 16 · 2021: 35 · 2020: 12 · 2019: 15 · 2018: 12 · 2017: 17 · 2016: 10 · 2015: 10 · 2014: 11 · 2013: 20 · 2012: 3
FWCI
9.43
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Human Molecular Genetics (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Research Portal (King's College London) (submittedVersion)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
Funders
  • U.S. Department of Health and Human Services
  • King Faisal Specialist Hospital and Research Centre
  • National Institutes of Health
  • Medical Research Council (G0501560, G0901254, MR/J006742/1)
  • National Institute on Aging (ZIAAG000932)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
Keywords
MAPT, tau gene, alternative splicing, regional gene expression, human brain, tauopathy, genetic risk factors, neurodegenerative diseases, progressive supranuclear palsy, corticobasal degeneration, Parkinson's disease, Alzheimer's disease
MeSH terms
Adolescent, Adult, Aged, Aged, 80 and over, Brain, Female, Frontal Lobe, Gene Expression Regulation, Haplotypes, Humans, Male, Middle Aged, Organ Specificity, Transcription, Genetic, Case-Control Studies, tau Proteins, Genetic Predisposition to Disease, Protein Isoforms, Polymorphism, Single Nucleotide, RNA Splice Sites, Tauopathies, Quantitative Trait Loci, INDEL Mutation, Young Adult, Genetic Association Studies

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