Abstract
Tauopathy, a major pathology in Alzheimer's disease, is also found in ∼50% of frontotemporal dementias (FTDs). Tau transcript, a product of a single gene, undergoes alternative splicing to yield 6 protein species, each with either 3 or 4 microtubule binding repeat domains (tau 3R or 4R, associated with dynamic and stable microtubules, respectively). While the healthy human brain shows a 1/1 ratio of tau 3R/4R, this ratio may be dramatically changed in the FTD brain. We have previously discovered that activity-dependent neuroprotective protein (ADNP) is essential for brain formation in the mouse, with ADNP+/− mice exhibiting tauopathy, age-driven neurodegeneration and behavioral deficits. Here, in transgenic mice overexpressing a mutated tau 4R species, in the cerebral cortex but not in the cerebellum, we showed significantly increased ADNP expression (∼3-fold transcripts) in the cerebral cortex of young transgenic mice (∼disease onset), but not in the cerebellum, as compared to control littermates. The transgene-age-related increased ADNP expression paralleled augmented dynamic tau 3R transcript level compared to control littermates. Blocking mutated tau 4R transgene expression resulted in normalization of ADNP and tau 3R expression. ADNP was previously shown to be a member of the SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex. Here, Brahma (Brm), a component of the SWI/SNF complex regulating alternative splicing, showed a similar developmental expression pattern to ADNP. Immunoprecipitations further suggested Brm-ADNP interaction coupled to ADNP - polypyrimidine tract-binding protein (PTB)-associated splicing factor (PSF)-binding, with PSF being a direct regulator of tau transcript splicing. It should be noted that although we have shown a correlation between levels of ADNP and tau isoform expression three months of age, we are not presenting evidence of a direct link between the two. Future research into ADNP/tau relations is warranted.
Highlights
Activity-dependent neuroprotective protein (ADNP) [1,2,3], a protein responsive to brain injury [4], [5,6] is essential for brain formation [7]
ADNP mRNA decreased at 5.5 months of age leveling with control values (Fig. 1C), at the protein level, there seemed to be a trend for increased expression of ADNP/actin ratio even at 5.5 months in the Tau-transgenic mice (Tg) mice compared to non-tau transgenic called here in short nontransgenic (non-Tg), this trend was insignificant (Fig. 1B)
To get an in depth answer for the ADNP-tau splicing regulation question, we have looked for ADNP-PSF and ADNP-Brm interaction in the cerebral cortex of 3-month-old ADNP+/+ and ADNP+/2 male mice
Summary
Activity-dependent neuroprotective protein (ADNP) [1,2,3], a protein responsive to brain injury [4], [5,6] is essential for brain formation [7]. Tau is characterized by the presence of a MT binding domain, which is composed of 3 or 4 repeats (3R and 4R tau) of a highly conserved tubulin binding motif (exon 10 on the tau gene encodes the additional tubulin binding site in the 4R tau). This domain comprises the carboxy terminal (C-terminal) half of the protein, followed by a basic proline-rich region and an acidic amino-terminal (N-terminal) region, which is normally referred to as the ‘projection domain’. Mutations in the tau gene have been identified in families suffering from hereditary FTD and Parkinsonism linked to chromosome 17 (FTDP-17) [24], [25]
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