Evidence for a role of the rare p.A152T variant in MAPT in increasing the risk for FTD-spectrum and Alzheimer's diseases

Abstract

Rare mutations in the gene encoding for tau (MAPT, microtubule-associated protein tau) cause frontotemporal dementia-spectrum (FTD-s) disorders, including FTD, progressive supranuclear palsy (PSP) and corticobasal syndrome, and a common extended haplotype spanning across the MAPT locus is associated with increased risk of PSP and Parkinson's disease. We identified a rare tau variant (p.A152T) in a patient with a clinical diagnosis of PSP and assessed its frequency in multiple independent series of patients with neurodegenerative conditions and controls, in a total of 15 369 subjects. Tau p.A152T significantly increases the risk for both FTD-s (n = 2139, OR = 3.0, CI: 1.6-5.6, P = 0.0005) and Alzheimer's disease (AD) (n = 3345, OR = 2.3, CI: 1.3-4.2, P = 0.004) compared with 9047 controls. Functionally, p.A152T (i) decreases the binding of tau to microtubules and therefore promotes microtubule assembly less efficiently; and (ii) reduces the tendency to form abnormal fibers. However, there is a pronounced increase in the formation of tau oligomers. Importantly, these findings suggest that other regions of the tau protein may be crucial in regulating normal function, as the p.A152 residue is distal to the domains considered responsible for microtubule interactions or aggregation. These data provide both the first genetic evidence and functional studies supporting the role of MAPT p.A152T as a rare risk factor for both FTD-s and AD and the concept that rare variants can increase the risk for relatively common, complex neurodegenerative diseases, but since no clear significance threshold for rare genetic variation has been established, some caution is warranted until the findings are further replicated.

Interplay of pathogenic forms of human tau with different autophagic pathways

“…However, whereas the P301L mutation leads to tau aggregation into paired helical filaments (PHFs) (Barghorn et al ., 2000), patients with the risk‐associated A152T mutation display higher abundance of oligomers (Coppola et al ., 2012). To analyze whether the differences in the behavior and cellular toxicity of these two tau mutants could be in part attributable to mutation‐specific changes in tau degradation, we first measured the contribution of CMA to their clearance.…”

“…We first compared two different mutations: P301L, known to cause autosomal‐dominant frontotemporal dementia (FTD) (Hutton et al ., 1998); and a point mutation of tau (A152T) that does not cause autosomal‐dominant disease but associates with higher risk of frontotemporal dementia and Alzheimer's disease (AD) (Coppola et al ., 2012). Our work reveals that both mutant forms of tau become poor e‐MI substrates and that P301L mutation, in addition, markedly reduces tau's susceptibility for CMA degradation.…”

Tau neurotoxicity and rescue in animal models of human Tauopathies

“…Pathological consequences of newly identified Tau mutations like the A152T [71] will add additional information about Tau mediated toxicity for other types of Tauopathy. Tau in oligodendrocytes is important during neuronglia contact formation which may link Tau dysfunction to developmental disorders [72].…”

Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer’s disease

“…Genotyping of the APOE allele (rs429358 and rs7412) was performed using a TaqMan Õ Allelic Discrimination Assay on an ABI 7900HT Fast Real-Time PCR system (Applied Biosystems) according to a previously described methodology (Coppola et al, 2012). APOE e4 status was determined in 19/ 20 patients.…”