The alternative splicing of tau exon 10 and its regulatory proteins CLK2 and TRA2‐BETA1 changes in sporadic Alzheimer's disease

Abstract

Pathological inclusions containing fibrillar aggregates of hyperphosphorylated tau protein are a characteristic feature in tauopathies, which include Alzheimer's disease (AD). Tau is a microtubule-associated protein whose transcript undergoes alternative splicing in the brain. Exon 10 encodes one of four microtubule-binding repeats. Exon 10 inclusion gives rise to tau protein isoforms containing four microtubule-binding repeats (4R) whereas exclusion leads to isoforms containing only three repeats (3R). The ratio between 3R and 4R isoforms is tightly controlled via alternative splicing in the human adult nervous system and distortion of this balance results in neurodegeneration. Previous studies showed that several splicing regulators, among them hTRA2-beta1 and CLK2, regulate exon 10 alternative splicing. Like most splicing factors, htra2-beta and clk2 pre-mRNAs are regulated by alternative splicing. Here, we investigated whether human postmortem brain tissue of AD patients reveal differences in alternative splicing patterns of the tau, htra2-beta, presenilin 2 and clk2 genes when compared with age-matched controls. We found that the splicing patterns of all four genes are altered in affected brain areas of sporadic AD patients. In these affected areas, the amount of mRNAs of tau isoforms including exon 10, the htra2-beta1 isoform and an inactive form of clk2 are significantly increased. These findings suggest that a misregulation of alternative splicing seems to contribute to sporadic AD.

Characterization of Nuclear Localization Signals (NLSs) and Function of NLSs and Phosphorylation of Serine Residues in Subcellular and Subnuclear Localization of Transformer-2β (Tra2β)

“…Tra2␤⌬RS1 isoform encodes a truncated protein containing the RRM, glycine linker and the RS2 domain. Tra2␤⌬RS1 expression is tissue-specific in both flies and mammals, and up-regulated by expression of Clk kinases and neural stimulation (26,49,50). So far, no distinct function has been assigned to the Tra2␤⌬RS1 isoform compared with the full-length Tra2␤, although this isoform is conserved in both vertebrates and invertebrates.…”

“…Tra2␤ is highly expressed in brain tissues and subject to developmental regulation in a tissue-and temporal-specific pattern (24). Tra2␤ controls the pre-mRNA splicing of the survival motor neuron (SMN) and tau genes (25)(26)(27)(28). Aberrant splicing of the genes is related to spinal muscular atrophy (SMA) and frontotemporal dementia (FTD), respectively.…”

Tau-Based Treatment Strategies in Neurodegenerative Diseases

“…63,64,212 No difference in the ratio of four-and three-repeat isoforms was found in total postmortem AD brain tau, but a roughly 1.5-fold excess of four-repeat tau has been reported in the temporal cortices of AD brains. 207,213,214 Four-repeat tau binds microtubules with a higher affinity than three-repeat tau, and an isoform imbalance in favor of four-repeat isoforms might impair kinesin-dependent anterograde traffic, because tau and kinesins bind to the microtubule surface in a competitive fashion. 28,30,146 Shifting the tau isoform ratio from fourrepeat to three-repeat isoforms by alternative splicing was therefore proposed as a therapeutic option in tauopathies.…”

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

“…Misregulation of tau exon 10 splicing causes inherited frontotemporal dementia with Parkinsonism (FTDP-17; Goedert and Jakes, 2005). Tau exon 10 misregulation has also been observed in sporadic AD (Glatz et al, 2006). Splicing is carried out by the spliceosome, a large and dynamic complex of proteins and small RNAs (Neubauer et al, 1998).…”