title: Presenilin controls CBP levels in the adult Drosophila central nervous system.
abstract: BACKGROUND
  Dominant mutations in both human Presenilin (Psn) genes have been correlated with the formation of amyloid plaques and development of familial early-onset Alzheimer's disease (AD). However, a definitive mechanism whereby plaque formation causes the pathology of familial and sporadic forms of AD has remained elusive. Recent discoveries of several substrates for Psn protease activity have sparked alternative hypotheses for the pathophysiology underlying AD. CBP (CREB-binding protein) is a haplo-insufficient transcriptional co-activator with histone acetly-transferase (HAT) activity that has been proposed to be a downstream target of Psn signaling. Individuals with altered CBP have cognitive deficits that have been linked to several neurological disorders.
  
  
  RESULTS
  Using a transgenic RNA-interference strategy to selectively silence CBP, Psn, and Notch in adult Drosophila, we provide evidence for the first time that Psn is required for normal CBP levels and for maintaining specific global acetylations at lysine 8 of histone 4 (H4K8ac) in the central nervous system (CNS). In addition, flies conditionally compromised for the adult-expression of CBP display an altered geotaxis behavior that may reflect a neurological defect.
  
  
  CONCLUSIONS
  Our data support a model in which Psn regulates CBP levels in the adult fly brain in a manner that is independent of Notch signaling. Although we do not understand the molecular mechanism underlying the association between Psn and CBP, our results underscore the need to learn more about the basic relationship between Psn-regulated substrates and essential functions of the nervous system.
authors.affiliation: School of Life Sciences, University of Nevada-Las Vegas, Las Vegas, Nevada, United States of America.
authors.forename: Randy S
authors.initials: RS
authors.lastname: Boyles
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Lantz
authors.forename: Steven
authors.initials: S
authors.lastname: Poertner
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Georges
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Andres
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D001921:Brain / Q000378:metabolism; D050882:CREB-Binding Protein / Q000096:biosynthesis* / Q000502:physiology; D002490:Central Nervous System / Q000378:metabolism*; D003433:Crosses, Genetic; D004330:Drosophila / Q000378:metabolism*; D005786:Gene Expression Regulation; D020868:Gene Silencing; D009154:Mutation; D010641:Phenotype; D053763:Presenilins / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction
chemical_list: D053763:Presenilins; D050882:CREB-Binding Protein