Variation in tau isoform expression in different brain regions and disease states

Abstract

Progressive supranuclear palsy (PSP) is the most common atypical parkinsonian disorder. Abnormal tau inclusions, in selected regions of the brain, are a hallmark of the disease and the H1 haplotype of MAPT, the gene encoding tau, is the major risk factor in PSP. A 3-repeat and 4-repeat tau isoform ratio imbalance has been strongly implicated as a cause of disease. Thus, understanding tau isoform regional expression in disease and pathology-free states is crucial to elucidating mechanisms involved in PSP and other tauopathies. We used a tau-isoform specific fluorescent assay to investigate relative 4R-tau expression in 6 different brain regions in PSP cases and healthy controls. We identified marked difference in 4R-tau relative expression, both across brain regions and between MAPT haplotypes. Highest 4R-tau expression levels were identified in the globus pallidus as compared to pons, cerebellum and frontal cortex. 4R-tau expression levels were related to both the MAPT H1 and H1c haplotypes. Similar regional variation was seen in both PSP cases and controls.

MAPT haplotype H1G is associated with increased risk of dementia with Lewy bodies

“…The H1 haplotype has been shown to be correlated to differential expression of the MAPT gene with H1 generally associated with increased MAPT expression in the brain. [20, 32, 33] H1 subhaplotypes have also been suggested to influence expression; among the suggestive associations to differential expression of MAPT are the H1B, H1I and H1L subhaplotypes in AD[20] and the H1C subhaplotype in PSP. [33] Interestingly, the H1 haplotype has been associated with differential expression, in addition to MAPT , of five other genes located at the MAPT locus: increased expression of MAPT , LRRC37A4 , and PLEKH1M and decreased expression of MGC57346 , LRRC37A and CRHR1 .…”

“…[20, 32, 33] H1 subhaplotypes have also been suggested to influence expression; among the suggestive associations to differential expression of MAPT are the H1B, H1I and H1L subhaplotypes in AD[20] and the H1C subhaplotype in PSP. [33] Interestingly, the H1 haplotype has been associated with differential expression, in addition to MAPT , of five other genes located at the MAPT locus: increased expression of MAPT , LRRC37A4 , and PLEKH1M and decreased expression of MGC57346 , LRRC37A and CRHR1 . [32] In PSP cases, H1 and H1C increased expression of MAPT appears to be correlated to increased levels of the 4R-tau isoforms which could be the basis for the imbalance in the 3R/4R tau ratio leading to the disease.…”

The effect of MAPT haplotype on neocortical Lewy body pathology in Parkinson disease

“…Inclusion of exon 10 leads to the production of 4R tau, which is more prone to aggregate. H1-encoded tau mRNA is more likely to contain exon 10 compared to H2-encoded transcripts (Caffrey et al 2006; Majounie et al 2013). Another alternative splicing event, inclusion of exon 3, inhibits tau aggregation, and H1-derived transcripts are less likely to contain exon 3 (Caffrey et al 2008; Trabzuni et al 2012).…”

Genome-wide association study identifies MAPT locus influencing human plasma tau levels

“…22 It has also been hypothesized that rs242557 could affect MAPT splicing, 20,23 although this has not been supported by subsequent studies. 24,25 Elevated plasma tau was not explained by elevated CSF tau. We did not identify a correlation between tau levels in plasma and CSF (figure 1), suggesting that different mechanisms are likely to regulate plasma tau concentrations.…”