Mutations in the tau gene that cause an increase in three repeat tau and frontotemporal dementia

Abstract

The majority of cases with frontotemporal dementia (FTD) have no tau deposition in the brain, yet mutations in the tau gene lead to a similar clinical phenotype with insoluble tau depositing in neuropathological lesions. We report two tau gene mutations at positions +19 and +29, in the intronic sequences immediately following the stem loop structure in exon 10, which segregate with FTD. Exon-trapping experiments showed that these gene mutations alter the splicing out of exon 10 and produce an increase in tau isoforms with three microtubule binding domains (three repeat tau). Mutagenesis experiments demonstrated that the +19 mutation was responsible for the increase in three repeat tau, possibly by altering an intron silencer modulator sequence element found at this region of the gene. Microtubule binding experiments revealed a significant decrease in microtubule assembly with increasing amounts of three and decreasing amounts of four repeat tau. Brain autopsy was available in one case. Analysis of the type of soluble tau isoforms revealed an increase in three repeat tau and an absence of tau isoforms with exon 3 inserts. No insoluble tau was isolated in the tissue fractions, consistent with the absence of tau-positive histopathology. There was also an increase in tau degradation products suggestive of increased proteolysis. This increase in tau breakdown products was associated with TUNEL- and activated caspase-3-positive neurons identified histologically. These studies show that increases in soluble three repeat tau can be responsible for FTD in cases with tau gene mutations in the intronic region immediately adjacent to the stem loop in exon 10. These cases of FTD have tau isoforms (without exon 3 inserts) that do not form abnormal aggregates and appear more prone to proteolysis. The increase in tau proteolysis was associated with increased evidence of apoptosis. This mechanism of neurodegeneration may be more applicable to the majority of FTD cases, which do not accumulate insoluble tau deposits.

SR protein 9G8 modulates splicing of tau exon 10 via its proximal downstream intron, a clustering region for frontotemporal dementia mutations

“…In this report we investigate the mechanism of action of SR protein 9G8, which inhibits inclusion of exon 10 ). Our results show that 9G8 directly interacts with the proximal downstream intron of exon 10, a clustering region for FTDP mutations (D 'Souza et al, 1999;Hutton et al, 1998;Stanford et al, 2003).…”

“…Exon 10 splicing is affected by exonic and intronic enhancers and silencers (D 'Souza et al, 1999;Schellenberg, 2000 D'Souza andSchellenberg, 2002;Gao et al, 2000;Grover et al, 1999;Hutton et al, 1998;Stanford et al, 2003;Wang et al, 2004), as well as by several trans factors and their phosphorylation (Broderick et al, 2004;Gao et al, 2000;Hartmann et al, 2001;Jiang et al, 2003;Kondo et al, 2004;Wang et al, 2004Wang et al, , 2005. Two regulatory elements and the factors that regulate them have been characterized within exon 10: an AT rich silencer that binds SRp30c and SRp55 which inhibit inclusion of exon 10 (Wang et al, 2005) and a purine-rich enhancer directly downstream of the silencer that binds htra2beta1 which activates inclusion of exon 10 (Jiang et al, 2003;Wang et al, 2005).…”

“…Investigations of dementia pedigrees have established that mutations in the downstream intron of exon 10 result in misregulation of tau exon 10 splicing and cause FTDP-17 (Goedert and Jakes, 2005;Hutton et al, 1998;Stanford et al, 2003). However, the regulators involved were unknown up to now.…”

Abolishing Tau cleavage by caspases at Aspartate421 causes memory/synaptic plasticity deficits and pre-pathological Tau alterations

“…Furthermore, several TAU mutations are genetically linked to fronto-temporal dementia (FTD). [5][6][7][8][9][10][11][12] Tau expression is regulated by alternative splicing in a speciesspecific, developmental-and tissue-dependent manner. [13][14][15][16] Depending upon the inclusion or exclusion of exon 10, Tau isoforms with three or four microtubule binding domains are generated (3R and 4R, respectively).…”

Stress in the brain: novel cellular mechanisms of injury linked to Alzheimer's disease

“…In cases of frontotemporal dementia, an increase in tau degradation was observed that was histologically associated with DNA fragmentation and caspase 3 activation in neurons [208]. Taken together with the biochemical data for the caspase processing of tau, these results suggest that tau cleavage may be a significant contributory factor in the pathogenesis of Alzheimer's disease.…”