Presenilin Controls CBP Levels in the Adult Drosophila Central Nervous System

Boyles, Randy S.; Lantz, Kathryn; Poertner, Steven; Georges, Stephanie; Andres, Andrew J.

doi:10.1371/journal.pone.0014332

Cited by 8 publications

(12 citation statements)

References 37 publications

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“…Using a ubiquitous driver, we first confirmed that our Psn shRNA lines result in 80-90% reduction of mRNA levels (Figure 1) and recapitulate developmental phenotypes of Psn germ-line mutant flies (Struhl and Greenwald 1999;Chung and Struhl 2001;Mahoney et al 2006). Consistent with notching wings in Notch heterozygous mutant flies, and in wing-specific Notch or Psn KD flies (Boyles et al 2010;Casso et al 2011), wing disc-specific expression of Psn shRNA leads to similar wing phenotypes at varying severity, allowing selection of the most effective Psn shRNA line (Figure 2). Selective neuronal expression of two independent Psn shRNA lines beginning at embryonic stages caused earlier lethality, rough eye phenotypes, and severe climbing defects (Figure 3 and Figure 4), and these phenotypes were partially rescued by expressing a Drosophila Psn transgene ( Figure 5).…”

Section: Discussionsupporting

confidence: 65%

An Evolutionarily Conserved Role of Presenilin in Neuronal Protection in the Aging Drosophila Brain

et al. 2017

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Mutations in the genes are the major genetic cause of Alzheimer's disease. Presenilin and Nicastrin are essential components of γ-secretase, a multi-subunit protease that cleaves Type I transmembrane proteins. Genetic studies in mice previously demonstrated that conditional inactivation of Presenilin or Nicastrin in excitatory neurons of the postnatal forebrain results in memory deficits, synaptic impairment, and age-dependent neurodegeneration. The roles of () and () in the adult fly brain, however, are unknown. To knockdown (KD) or selectively in neurons of the adult brain, we generated multiple shRNA lines. Using a ubiquitous driver, these shRNA lines resulted in 80-90% reduction of mRNA and pupal lethality-a phenotype that is shared with and mutants carrying nonsense mutations. Furthermore, expression of these shRNAs in the wing disc caused notching wing phenotypes, which are also shared with and mutants. Similar to , neuron-specific KD using two independent shRNA lines led to early mortality and rough eye phenotypes, which were rescued by a fly transgene. Interestingly, conditional KD (cKD) of or in adult neurons using the and system caused shortened lifespan, climbing defects, increases in apoptosis, and age-dependent neurodegeneration. Together, these findings demonstrate that, similar to their mammalian counterparts, Psn and Nct are required for neuronal survival during aging and normal lifespan, highlighting an evolutionarily conserved role of Presenilin in neuronal protection in the aging brain.

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Section: Discussionsupporting

confidence: 65%

An Evolutionarily Conserved Role of Presenilin in Neuronal Protection in the Aging Drosophila Brain

et al. 2017

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“…In mammalian models, these functions include stabilizing the binding of CTNNB1 and GSK3β, where Alzheimer disease causing mutations result in reduced stability of CTNNB1 [18,19,25,26], and in endoplasmic reticulum (ER) calcium regulation [27,28]. In D. melanogaster, presenilin proteins have been found to modulate the levels of CREBBP (cyclic-AMP Response Element Binding protein) independently of proteolytic activity [29]. A similar non-proteolytic function for presenilin proteins or the γ-secretase complex has also been proposed in both C. elegans [30] and the moss P. patens [20].…”

Section: Introductionmentioning

confidence: 99%

Gamma secretase orthologs are required for lysosomal activity and autophagic degradation in Dictyostelium discoideum, independent of PSEN (presenilin) proteolytic function

et al. 2019

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Mutations in the γ-secretase complex are strongly associated with familial Alzheimer disease. Both proteolytic and non-proteolytic functions for the γ-secretase complex have been previously described in mammalian model organisms, but their relative contributions to disease pathology remain unclear. Here, we dissect the roles of orthologs of the γ-secretase components in the model system Dictyostelium, focusing on endocytosis, lysosomal activity and autophagy. In this model, we show that the orthologs of PSEN (psenA and psenB), Ncstn (nicastrin) and Aph-1 (gamma-secretase subunit Aph-1), are necessary for optimal fluid-phase uptake by macropinocytosis and in multicellular development under basic pH conditions. Disruption of either psenA/B or Aph-1 proteins also leads to disrupted phagosomal proteolysis as well as decreased autophagosomal acidification and autophagic flux. This indicates a general defect in lysosomal trafficking and degradation, which we show leads to the accumulation of ubiquitinated protein aggregates in cells lacking psenA/B and Aph-1 proteins. Importantly, we find that all the endocytic defects observed in Dictyostelium PSEN ortholog mutants can be fully rescued by proteolytically inactive Dictyostelium psenB and human PSEN1 proteins. Our data therefore demonstrates an evolutionarily conserved non-proteolytic role for presenilin, and γ-secretase component orthologs, in maintaining Dictyostelium lysosomal trafficking and autophagy.

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“…Kilgore, et al (2010), for example, demonstrated that memory deficits in the APPswe/PS1dE9 double-transgenic mouse model are reversed by HDAC1 inhibitor administration. CBP protein expression is decreased in a forebrain-specific double presenilin conditional knockout mouse (Saura, et al, 2004), and in flies, CBP levels in the central nervous system are reduced in the absence of presenilin (Boyles, et al, 2010). Furthermore, Rouaux, et al (2003) and Saha, et al (2009) found that CBP levels are decreased during neuronal apoptosis and that increasing expression can protect against toxic insults.…”

Section: Discussionmentioning

confidence: 99%

CREB-binding protein levels in the rat hippocampus fail to predict chronological or cognitive aging

Pereira

Coletta

Perez

et al. 2013

Neurobiology of Aging

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Normal cognitive aging is associated with deficits in memory processes dependent on the hippocampus, along with large-scale changes in the hippocampal expression of many genes. Histone acetylation can broadly influence gene expression and has been recently linked to learning and memory. We hypothesized that cAMP response element binding (CREB)-binding protein (CBP), a key histone acetyltransferase, may contribute to memory decline in normal aging. Here, we quantified CBP protein levels in the hippocampus of young, aged unimpaired and aged impaired rats, classified on the basis of spatial memory capacity documented in the Morris water maze. First, CBP-immunofluorescence was quantified across the principal cell layers of the hippocampus using both low and high resolution laser scanning imaging approaches. Second, digital images of CBP immunostaining were analyzed by a multi-purpose classifier algorithm (WND-CHARM) with validated sensitivity across many types of input materials. Finally, CBP protein levels in the principal subfields of the hippocampus were quantified by quantitative western blotting. CBP levels were equivalent as a function of age and cognitive status in all analyses. The sensitivity of the techniques used was substantial, sufficient to reveal differences across the principal cell fields of the hippocampus, and to correctly classify images from young and aged animals independent of CBP-immunoreactivity. The results are discussed in the context of recent evidence suggesting that CBP decreases may be most relevant in conditions of aging that, unlike normal cognitive aging, involve significant neuron loss.

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Presenilin Controls CBP Levels in the Adult Drosophila Central Nervous System

Cited by 8 publications

References 37 publications

An Evolutionarily Conserved Role of Presenilin in Neuronal Protection in the Aging Drosophila Brain

An Evolutionarily Conserved Role of Presenilin in Neuronal Protection in the Aging Drosophila Brain

Gamma secretase orthologs are required for lysosomal activity and autophagic degradation in Dictyostelium discoideum, independent of PSEN (presenilin) proteolytic function

CREB-binding protein levels in the rat hippocampus fail to predict chronological or cognitive aging

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