Neuroscience 2001 Abstract
| Presentation Number: | 542.12 |
|---|---|
| Abstract Title: | A Model of Tau Exon 10 Splicing in Neurodegenerative Disease. |
| Authors: |
Grover, A.*1
; Adamson, J.1
; Hutton, M.1
1Dept. Neuroscience, Mayo Clinic, Jacksonville, FL |
| Primary Theme and Topics |
Neurological and Psychiatric Conditions - Neurodegenerative Disorders -- Alzheimers Disease: Tau |
| Session: |
542. Neurodegenerative disorders: Alzheimer's disease: tau--molecular studies Poster |
| Presentation Time: | Tuesday, November 13, 2001 11:00 AM-12:00 PM |
| Location: | Exhibit Hall WW-49 |
| Keywords: | NEURODEGENERATION, FRONTO-TEMPORAL DEMENTIA, PROGRESSIVE SUPRANUCLEAR PALSY, MINIGENE |
Tau pathology is associated with the development of such neurodegenerative diseases as Fronto-temporal Dementia with Parkinsonism linked to Chromosome 17 (FTDP-17), Progressive Supranuclear Palsy (PSP)and Cortico-Basal Degeneration (CBD). Exon 10 (E10) of Tau encodes one of four imperfect repeat microtubule binding domains. It is alternatively spliced in the adult human brain, creating proteins with either three (3R) or four (4) repeats. Mutations associated with FTDP-17 close to the 5'-slice site of E10 have been shown to increase the inclusion of E10 in tau mRNA, and therefore 4R Tau protein.
We constructed a minigene incorporating E9 and E11 with ~100bp of flanking intronic sequence, and E10 with ~1kb of intronic sequence flanking E10. We show that the minigene the ratio of E10+.E10- closely approximates that seen in human brain when expressed in neuronal, but not non-neuronal cell lines. Mutations known to cause FTDP-17 through alterations in splicing of E10 in vivo are shown to affect the splicing of the minigene in a similar fashion. We demonstrate using deletion constructs that elements exist within the intronic sequence around exon 10 that can influence the ratio of splicing of E10, and investigate further their effects on alternative splicing of this exon.
Also, the region of Chromosome 17 that includes the tau gene has two distinct extended haplotype families, called H1 and H2. Association studies show the H1 haplotype to be significantly over-represented in people suffering from PSP. We created minigenes that incorporate the H1/H2 polymorphisms within E9, I9 and E11 and compared the splicing behaviour of each minigene under the influence of a number of promoters, including the tau promoter.
We constructed a minigene incorporating E9 and E11 with ~100bp of flanking intronic sequence, and E10 with ~1kb of intronic sequence flanking E10. We show that the minigene the ratio of E10+.E10- closely approximates that seen in human brain when expressed in neuronal, but not non-neuronal cell lines. Mutations known to cause FTDP-17 through alterations in splicing of E10 in vivo are shown to affect the splicing of the minigene in a similar fashion. We demonstrate using deletion constructs that elements exist within the intronic sequence around exon 10 that can influence the ratio of splicing of E10, and investigate further their effects on alternative splicing of this exon.
Also, the region of Chromosome 17 that includes the tau gene has two distinct extended haplotype families, called H1 and H2. Association studies show the H1 haplotype to be significantly over-represented in people suffering from PSP. We created minigenes that incorporate the H1/H2 polymorphisms within E9, I9 and E11 and compared the splicing behaviour of each minigene under the influence of a number of promoters, including the tau promoter.
Supported by NIA
Sample Citation:
[Authors]. [Abstract Title]. Program No. XXX.XX. 2001 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience, 2001. Online.
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