The biochemical parameters of tau pathology

6) Tau mutations, tau polymorphisms and tau abnormal splicing

The presence of brain lesions in neurodegenerative disorders usually arouses the same question: is this a cause or a consequence? Some answers are already available for tau pathology. The discovery that tau mutations are directly involved in numerous FTDP-17 has been dramatically documented. More than 20 different mutations have been spotted. Most of the pathogenic mutations are responsible for an increase of 4R tau isoforms, giving a class II tau pathology. 4R tau isoforms, with the additional peptidic sequence of exon 10, have a much stronger affinity toward microtubules than 3R isoforms, and an excess could modify microtubules properties, which will be stiffer and less dynamic. The other mutations are missense mutations that also affect microtubule polymerization and stability by decreasing tau–microtubule binding and lead to one of the class I, II, III tau pathologies. The striking feature of these familial tauopathies is the heterogeneity of the phenotype, which results from the different effects on tau (overexpression, loss of function). Surprisingly, for the same mutation in the same family, different onsets and different phenotypes can be observed, showing that numerous additional factors are modulating the clinical and neuropathological features.

We note that the neuropathological profile in FTDP-17 is quite different from AD, with a special involvement of astrocytes and cortical white matter, but also with an important heterogeneity for each mutation.

However, not all diseases with a tau pathology have mutations on the tau gene. This has been verified for CBD, PSP, amyotrophic lateral sclerosis/parkinsonism dementia complex of Guam, and AD.

All these mutations can be tested on a very efficient and relevant model

Delobel P, Flament S, Hamdane M, Jakes R, Rousseau A, Delacourte A, Vilain JP, Goedert M, Buee L. Functional characterization of FTDP-17 tau gene mutations through their effects on Xenopus oocyte maturation. J Biol Chem 2002;277:9199-205.

Conrad and colleagues (Conrad et al. 1998) identified a polymorphic dinucleotide repeat sequence in a Caucasian population with PSP. This polymorphism, named A0, corresponding to an 11 TG dinucleotide repeat in intron 9 of the tau gene, is found in 95% of the PSP cohort (95.5%) and only in 57% of normal controls and 50% of patients with AD. Recently, these data were confirmed by several studies and extended to a haplotype including a number of polymorphisms in linkage disequilibrium with A0 and named H1. This haplotype corresponds to A0 polymorphism, numerous single nucleotide polymorphisms along the entire tau gene and one intronic 238 bp deletion flanking exon 10. These polymorphisms may influence exon 10 splicing and thus the proportion of 4R : 3R tau isoforms, leading to a class II tau pathology. It should be noted that these A0 polymorphisms or H1 haplotypes were recently described in other pathologies including CBD and Parkinson’s disease. Some other polymorphisms in the tau gene were also described as being associated with a risk of AD, but these data are still controversial (reviewed in (Delacourte and Buée 2000).

See tauHaplotypes

Abnormal splicing in tauopathies

A) Direct abnormal splicing

Mutations in the intron 10 of tau gene provoke an increase production of exon 10 isoforms

B) Indirect abnormal splicing

Abnormal number of CTG repeats on chromosome 19 provokes an abnormal splicing of different proteins, including tau.

Sergeant N, Sablonniere B, Schraen-Maschke S, Ghestem A, Maurage CA, Wattez A, Vermersch P, Delacourte A.

Related Articles

Dysregulation of human brain microtubule-associated tau mRNA maturation in myotonic dystrophy type 1.
Hum Mol Genet. 2001 Sep 15;10(19):2143-55.
PMID: 11590131

reprint of the HMG paper

Six main features define tau pathology: 

• 1) the quantitative aspects, using western blots ; 

• 2) the different biochemical signatures observed in AD, PSP, CBD, PiD, MyoD (one to four immunodetected electrophoretic bands); 

• 3) the specific tau isoforms content of brain lesions. Indeed, "disease-specific" sets of tau isoforms aggregate to constitute 4 main categories of tau lesions: class 1: AD (all 6 isoforms), class 2: PSP/CBD (3 Exon10+ isoforms), class 3: PiD (3 Exon10- isoforms) and class 4: MyoD (mainly and sometimes exclusively the shortest tau isoform); 

• 4) the different states of phosphorylation of tau, with hyper and abnormal phosphorylation, as well as disease-specific sites of phosphorylation (ex: ser262); 

• 5) the spatiotemporal progression of tau pathology, which is extremely well correlated with cognitive impairment; 

• 6) the genetic aspects, with pathogenic tau mutations in FTDP-17 or characteristic polymorphisms in PSP. 

References