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P3‐139: Differential regulation of the alternative splicing of tau exon 10 by protein kinase A isoforms
Author(s) -
Shi Jianhua,
Qian Wei,
Yin Xiaomin,
GrundkeIqbal Inge,
Iqbal Khalid,
Gong ChengXin,
Liu Fei
Publication year - 2011
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2011.05.1579
Subject(s) - exon , gene isoform , alternative splicing , rna splicing , tau protein , microbiology and biotechnology , hek 293 cells , chemistry , protein kinase a , protein subunit , biology , phosphorylation , gene , biochemistry , rna , alzheimer's disease , medicine , disease
motif, alone or co-transfected together with Flag-TDP-43 or siRNA targeting TDP-43. Results: Interestingly, we observed a bimodal effect of TDP43 on tau gene expression. In undifferentiated cells, TDP-43 overexpression resulted in increased levels of tau protein whereas in retinoic acid differentiated cells we noticed the opposite effect. The appearance of tau higher molecular weight isoforms would also suggest that TDP-43 may affect splicing of the alternatively spliced MAPT exons. Using luciferase reporter vectors for the MAPT promoter regions containing the putative TDP-43 binding site, we show that overexpression of TDP-43 significantly represses MAPT transcription for all three MAPT haplotypes H1b, H1c and H2, whereas an opposite effect is observed knocking-down TDP-43. Conclusions: Our results suggest a crucial role for TDP-43 in tau gene expression regulation at both RNA and protein level, which might be dependent on the cellular differentiation state.