Tra2 beta, SF2/ASF and SRp30c modulate the function of an exonic splicing enhancer in exon 10 of tau pre-mRNA

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) is associated with mutations in the tau gene.
• Aberrant alternative splicing of tau exon 10, encoding a microtubule-binding motif, is implicated in FTDP-17 pathogenesis.

Purpose of the Study:

• To investigate the molecular mechanisms underlying aberrant tau gene splicing in FTDP-17.
• To determine how FTDP-17-linked mutations impact the splicing regulatory elements of tau exon 10.

Main Methods:

• Exon trapping assays were employed to analyze tau exon 10 splicing.
• In vitro splicing assays using a dsx-substrate were performed.
• Nuclear extracts from neuroblastoma cell lines were used to assess protein binding to tau pre-mRNA.

Main Results:

• Tau exon 10 (nucleotides 12-45) exhibits exonic splicing enhancer (ESE) activity.
• FTDP-17-linked mutations were found to impair ESE activity, leading to altered tau exon 10 splicing patterns.
• SR proteins, including Tra2 beta and ASF/SF2, bind to the wild-type tau exon 10 ESE; their binding increased with the N279K mutation, enhancing mutant tau exon 10 splicing. SRp30c also enhanced splicing.

Conclusions:

• FTDP-17-associated mutations in tau exon 10 disrupt ESE activity.
• Altered binding of SR proteins to tau pre-mRNA is a key mechanism underlying aberrant splicing in FTDP-17.