FE65 Binds Teashirt, Inhibiting Expression of the Primate-Specific Caspase-4

• DOI: 10.1371/journal.pone.0005071
• Publication Date: 2009-04-02T22:45:31Z
• Authors: Yuji Kajiwara; Afia Akram; Pavel Katsel; Vahram Haroutunian; James Schmeidler; Gary Beecham; Jonathan L. Haines; Margaret A. Peric...; Joseph D. Buxbaum
• Keywords: Chromatin immunoprecipitation

The Alzheimer disease (AD) amyloid protein precursor (APP) can bind the FE65 adaptor and this complex regulate gene expression. We carried out yeast two-hybrid studies with a PTB domain of FE65, focusing on those genes that might be involved in nuclear signaling, identified validated Teashirt proteins as interacting neurons. Using reporter systems, we observed could simultaneously recruit SET, component inhibitor acetyl transferase, Teashirt, which turn recruited histone deacetylases, to produce powerful gene-silencing complex. screened stable cell lines macroarray AD-related CASP4, encoding caspase-4, target silencing Chromatin immunoprecipitation showed direct interaction Teashirt3 promoter region CASP4. Expression postmortem samples demonstrated decreasing expression increasing caspase-4 progressive cognitive decline. Importantly, there were significant increases associated even earliest neuritic plaque changes AD. evaluated case-control cohort evidence for genetic association between TSHZ1 TSHZ3 AD, SNP genotype correlating Teashirt3. results consistent model reduced Teashirt3, mediated by or other causes, expression, leading progression Thus biological, data support role Teashirt/caspase-4 AD biology. As shows being primate-specific gene, current models neurodegenerative conditions may incomplete because absence murine genome.