Frontotemporal dementia with Parkinsonism linked to Chromosome 17

Frontotemporal dementia with Parkinsonism linked to Chromosome 17 (FTDP-17) is an autosomal dominant neurodegenerative disorder. It is characterised by behavioural and personality changes, cognitive impairment, and motor symptoms.

It is caused by the mutation in the tau gene that encodes microtuble associated protein Tau. In patients with FTDP-17 it shows abnormal intracellular accumulation of anomalous filaments that contain the microtubule associated protein tau. The prevalence and incidence remain unknown but FTDP-17 is an extremely rare condition.

Molecular cause and consequences

The microtuble associated protein Tau is encoded by a single gene (MAPT) located on chromosome 17. The gene undergoes extensive alternative splicing and eight of the 16 exons are alternatively spliced.

In humans, these splicing events are spatially and temporally regulated. For example, exons 2, 3 and 10 are adult specific and show differences in splicing in various brain regions. The tau protein binds to microtubles via microbuble repeat regions. One of these microtuble binding regions is encoded by the alternatively used exon 10. Exon 10 inclusion creates a protein with four microtuble repeats (4R), whereas exon 10 skipping creates an isoform with three repeats (3R).

Genetic studies that identified rare dominant mutations in the tau gene (microtuble associated protein tau) that caused frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), are collected on the AD&FTD Mutation Database website and currently list 42 mutations. The majority of the mutations affect the splicing regulation of exon 10 that encodes part of one microtuble binding site.

The exon shows an alternating arrangement of four enhancer and three silencer regions. A mutation that falls into a silencer or enhancer regions either promotes or decreases exon usage, respectively. Mutations in exon 10 alter its normal fraction of inclusion and changes of pre-mRNA encoding 3R and 4R repeat tau isoforms were found associated with FTDP-17. These data clearly suggested that the splicing mutations cause the neuropathology by changing the ratio between the 3R and 4R isoforms.

Gene's structure and Alternative Splicing (AS) events

View the full gene diagram and AS pattern of MAPT on the Fast DB website.

Molecular approaches to diagnoses and therapy

Testing in mouse models is difficult, as the mouse tau gene constitutively expresses the 4R isoform in the adult. Therefore, a minigene of human tau, containing the promoter and all exons flanked by shortend intronic regions was expressed in mice. These constructs show alternative splicing resembling the human situation and express human tau protein containing either 3 or 4 microtuble binding domains. When the mutation that promotes exon 10 inclusion was introduced into exon 10 of this construct, pre-mRNA splicing was shifted as expected towards exon 10 inclusion. Interestingly, the mice showed similar pathophysiology as humans with the same mutation and also showed behavioral changes. These data suggest that a change in the ratio between 3R and 4R tau isoforms is an important underlying cause for FTDP-17.

EURASNET contact:

Stefan Stamm:

Based on ‘Alternative splicing and disease’ Tazi, J., Bakkour, N., Stamm, S. Biochimica et Biophysica Acta. 2009 Jan;1792(1):14-26. Epub 2008 Oct 17.