Haplotype-specific MAPT exon 3 expression regulated by common intronic polymorphisms associated with Parkinsonian disorders

Lai, Mang Ching; Bechy, Anne-Laure; Denk, Franziska; Collins, Emma; Gavriliouk, Maria; Zaugg, Judith B.; Ryan, Brent J.; Wade‐Martins, Richard; Caffrey, Tara M.

doi:10.1186/s13024-017-0224-6

Cited by 14 publications

(11 citation statements)

References 74 publications

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“…We were unable to identify regulators of MAPT exon 3 splicing from these data, or to compare its regulation between 17q21.31 H1 and H2 haplotypes due to the low frequency of H2 carriers. Increased Exon 3 inclusion is consistently identified on the H2 background 12, 39 , an effect we also observe in these data. However, the mechanism underlying increased exon 3 inclusion, and whether its expression is protective against tauopathy is currently unknown, although it may reduce the fibrillization of tau 52 .…”

Section: Discussionsupporting

confidence: 82%

Dysregulated coordination ofMAPTexon 2 and exon 10 splicing underlies different tau pathologies in PSP and AD

Bowles

Pugh

Oja

et al. 2021

Preprint

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Understanding regulation of MAPT splicing is important to the etiology of many nerurodegenerative diseases, including Alzheimer disease (AD) and progressive supranuclear palsy (PSP), in which different tau isoforms accumulate in pathologic inclusions. MAPT, the gene encoding the tau protein, undergoes complex alternative pre-mRNA splicing to generate six isoforms. Tauopathies can be categorized by the presence of tau aggregates containing either 3 (3R) or 4 (4R) microtubule binding domain repeats (determined by inclusion/exclusion of exon 10), but the role of the N terminal domain of the protein, determined by inclusion/exclusion of exons 2 and 3 has been less well studied. Using an unbiased correlational screen in human brain tissue, we observed coordination of MAPT exons 2 and 10 splicing. Expression of exon 2 splicing regulators and subsequently exon 2 inclusion are differentially disrupted in PSP and AD brain, resulting in the accumulation of 1N4R isoforms in PSP and 0N isoforms in AD temporal cortex. Furthermore, we identified different N-terminal isoforms of tau present in neurofibrillary tangles, dystrophic neurites and tufted astrocytes, indicating a role for differential N-terminal splicing in the development of disparate tau neuropathologies. We conclude that N-terminal splicing and combinatorial regulation with exon 10 inclusion/exclusion is likely to be important to our understanding of tauopathies.

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Section: Discussionsupporting

confidence: 82%

Dysregulated coordination ofMAPTexon 2 and exon 10 splicing underlies different tau pathologies in PSP and AD

Bowles

Pugh

Oja

et al. 2021

Preprint

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“…The MAPT locus, found on chromosome 17, represents one of the largest LD blocks in the human genome (1.8 Mb) and is present in two distinct haplotypes, H1 and H2, the latter formed by an approximately 900 kb inversion of H1 that occurred about 3 million years ago and is present mostly in Europeans 51 . Cumulatively, previous work supports MAPT haplotype-specific impacts on transcript amount, transcript stability, and alternative splicing in several neurodegenerative disorders 54, 56, 57 . We highlight multiple epigenetic avenues through which the MAPT gene is differentially regulated in the H1 and H2 haplotypes, thus explaining at least a portion of the molecular underpinnings of the observed MAPT GWAS association in PD.…”

Section: Discussionmentioning

confidence: 54%

“…The MAPT locus is present within a large 1.8-Mb LD block and manifests as two distinct haplotypes, H1 and H2, which differ genetically in two primary ways: (i) more than 2000 SNPs differ across the two haplotypes, and (ii) an approximately 1-Mb inversion that includes the MAPT gene 51, 52 (Figure 6a). Previous reports have nominated multiple explanations for how these alterations are associated with PD, including increased MAPT expression in the H1 haplotype 53, 54 (Figure 6b), different ratios of splice isoforms 55–57 , and the use of alternative promoters 58 . We created a haplotype-specific map of chromatin accessibility and 3D chromatin interactions at the MAPT locus (Figure 6c).…”

Section: Resultsmentioning

confidence: 99%

Single-cell epigenomic identification of inherited risk loci in Alzheimer’s and Parkinson’s disease

Corces

Shcherbina

Kundu

et al. 2020

Preprint

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42Genome-wide association studies (GWAS) have identified thousands of variants associated with 43 disease phenotypes. However, the majority of these variants do not alter coding sequences, making 44 it difficult to assign their function. To this end, we present a multi-omic epigenetic atlas of the 45 adult human brain through profiling of the chromatin accessibility landscapes and three-46 dimensional chromatin interactions of seven brain regions across a cohort of 39 cognitively healthy 47 individuals. Single-cell chromatin accessibility profiling of 70,631 cells from six of these brain 48 regions identifies 24 distinct cell clusters and 359,022 cell type-specific regulatory elements, 49 capturing the regulatory diversity of the adult brain. We develop a machine learning classifier to 50 integrate this multi-omic framework and predict dozens of functional single nucleotide 51 polymorphisms (SNPs), nominating gene and cellular targets for previously orphaned GWAS loci. 52These predictions both inform well-studied disease-relevant genes, such as BIN1 in microglia for 53 Alzheimer's disease (AD) and reveal novel gene-disease associations, such as STAB1 in microglia 54 and MAL in oligodendrocytes for Parkinson's disease (PD). Moreover, we dissect the complex 55 inverted haplotype of the MAPT (encoding tau) PD risk locus, identifying ectopic enhancer-gene 56 contacts in neurons that increase MAPT expression and may mediate this disease association. This 57 work greatly expands our understanding of inherited variation in AD and PD and provides a 58 roadmap for the epigenomic dissection of noncoding regulatory variation in disease. 59 60 61 62Alzheimer's disease (AD) and Parkinson's disease (PD) affect ~50 and ~10 million individuals 63 world-wide, as two of the most common neurodegenerative disorders. Several large consortia have 64 assembled genome-wide association studies (GWAS) that associate genetic variants with clinical 65 diagnoses of probable AD dementia 1-4 or probable PD 5-7 , or with their characteristic pathologic 66 features. These efforts have led to the identification of dozens of potential risk loci for these 67 prevalent neurodegenerative diseases. One goal of these studies was to build more precise 68 molecular biomarkers of AD or PD, efforts that are beginning to yield encouraging results with 69 polygenic risk scores 8 . The other major goal was to gain deeper insight into the molecular 70 pathogenesis of disease and thereby inform novel therapeutic targets. Some of the risk loci contain 71 coding variants and so have credibility as putative disease mediators. However, most risk loci are 72 in noncoding regions and so it remains unclear if the nominated (often nearest) gene is the 73 functional disease-relevant gene, or if some other gene is involved 9 . Furthermore, even if the 74 nominated gene is a true positive, the noncoding risk locus might regulate additional genes. These 75 challenges remain a fundamental gap in interpreting the etiology of neurodegenerative diseases 76 and d...

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“…Based on a region of linkage disequilibrium, allele calls were mapped to their respective MAPT haplotype. 33 Statistical analyses were performed using SAS v9.4 (SAS Institute, Cary, NC, USA). The Wilcoxon Mann-Whitney U test was utilized to determine the difference between the ages of the control cohort compared to the five disease cohorts of interest.…”

Section: Methodsmentioning

confidence: 99%

Genetic Variation in the Ontario Neurodegenerative Disease Research Initiative

Dilliott

Evans

Farhan

et al. 2019

Can. J. Neurol. Sci.

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ABSTRACT:Background/Objective:Apolipoprotein E (APOE) E4 is the main genetic risk factor for Alzheimer’s disease (AD). Due to the consistent association, there is interest as to whether E4 influences the risk of other neurodegenerative diseases. Further, there is a constant search for other genetic biomarkers contributing to these phenotypes, such as microtubule-associated protein tau (MAPT) haplotypes. Here, participants from the Ontario Neurodegenerative Disease Research Initiative were genotyped to investigate whether the APOE E4 allele or MAPT H1 haplotype are associated with five neurodegenerative diseases: (1) AD and mild cognitive impairment (MCI), (2) amyotrophic lateral sclerosis, (3) frontotemporal dementia (FTD), (4) Parkinson’s disease, and (5) vascular cognitive impairment.Methods:Genotypes were defined for their respective APOE allele and MAPT haplotype calls for each participant, and logistic regression analyses were performed to identify the associations with the presentations of neurodegenerative diseases.Results:Our work confirmed the association of the E4 allele with a dose-dependent increased presentation of AD, and an association between the E4 allele alone and MCI; however, the other four diseases were not associated with E4. Further, the APOE E2 allele was associated with decreased presentation of both AD and MCI. No associations were identified between MAPT haplotype and the neurodegenerative disease cohorts; but following subtyping of the FTD cohort, the H1 haplotype was significantly associated with progressive supranuclear palsy.Conclusion:This is the first study to concurrently analyze the association of APOE isoforms and MAPT haplotypes with five neurodegenerative diseases using consistent enrollment criteria and broad phenotypic analysis.

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Haplotype-specific MAPT exon 3 expression regulated by common intronic polymorphisms associated with Parkinsonian disorders

Cited by 14 publications

References 74 publications

Dysregulated coordination ofMAPTexon 2 and exon 10 splicing underlies different tau pathologies in PSP and AD

Dysregulated coordination ofMAPTexon 2 and exon 10 splicing underlies different tau pathologies in PSP and AD

Single-cell epigenomic identification of inherited risk loci in Alzheimer’s and Parkinson’s disease

Genetic Variation in the Ontario Neurodegenerative Disease Research Initiative

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