Localization of presenilin-1 mRNA in rat brain

Quarteronet, Dominique; Pradier, Laurent; Czech, Christian; Delalonde, Laurence; Burgevin, Marie-Claude; Doble, Adam; Petitet, François

doi:10.1097/00001756-199611040-00036

Cited by 15 publications

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“…Hence the identification of the mechanisms controlling the expression of the PS1 gene should relate directly to understanding further the development and differentiation pathways and the pathogenesis of FAD. PS1 is differentially expressed in a variety of tissues [2] and brain expression is restricted to neurons [7–11]. We have previously identified the promoter sequences controlling the basal expression of the PS1 gene [12].…”

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confidence: 99%

Activation of transcription of the human presenilin 1 gene by 12‐O‐tetradecanoylphorbol 13‐acetate

Pastorcic

Das

2002

European Journal of Biochemistry

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We have recently identified an Ets element controlling over 90% of the basal expression of the human presenilin 1 (PS1) gene. We have also shown that Ets1 and Ets2 act as transactivators of the PS1 gene by cotransfection experiments in SK-N-SH neuronal cells. The PS1 gene is widely but differentially expressed across tissues and the expression in brain appears to be restricted to neurons. To gain further insight into the regulation of the gene we have examined the regulation of PS1 by 12-O-tetradecanoylphorbol 13-acetate (TPA). SK-N-SH neuronal cells were treated with 0.2 micro m TPA for 30 min to 24 h and the level of expression of the endogenous PS1 gene was measured by Northern blot analysis. A two- to threefold increase in the level of PS1 mRNA appeared 4-8 h after the addition of TPA. A similar increase in transcription activity was observed in nuclear run off experiments, indicating that the increased mRNA level results from an activation in the initiation of transcription of PS1. Consistently, TPA also increased the level of PS1 protein. No activation of the PS1 endogenous gene by TPA was observed in hepatoma HepG2 cells. Next we tested the effect of TPA on the expression of the PS1 promoter by transfecting fusion genes including various fragments of the PS1 promoter linked to a CAT reporter into SK-N-SH cells. TPA also stimulated the expression of the PS1CAT constructs. Generally wild type constructs -687/+178, -118/+178, -22/+178 including the short -35/+6 fragment showed a minor two- to threefold activation by TPA. Point mutations eliminating the -10 Ets motif or the -6 CREB/AP1 motif did not decrease the stimulation by TPA. Thus TPA appears to activate the transcription of the PS1 gene by a mechanism which does not require these elements.

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confidence: 99%

Activation of transcription of the human presenilin 1 gene by 12‐O‐tetradecanoylphorbol 13‐acetate

Pastorcic

Das

2002

European Journal of Biochemistry

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“…PS-1 expression is higher in the hippocampus and cerebellum than in the cerebral cortex (29 -32). Hippocampal pyramidal neurons, dentate granule neurons, cerebellar Purkinje neurons, and primary olfactory cortical neurons show higher PS-1 expression than the neurons in other cortical regions of rat brain (33,34). Compared with the adult, the level of PS-1 expression is significantly higher in the developing rat brain.…”

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confidence: 87%

Activated cAMP-response Element-binding Protein Regulates Neuronal Expression of Presenilin-1

Mitsuda

Ohkubo

Tamatani

et al. 2001

Journal of Biological Chemistry

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Alzheimer's disease is a devastating neurological disorder characterized by progressive memory loss and cognitive deficits. To date, four genes have been found to be associated with Alzheimer's disease phenotypes including the amyloid precursor protein gene on chromosome 21 (1-4), the apolipoprotein E gene on chromosome 19 (5-7), the presenilin-1 (PS-1) 1 gene on chromosome 14 (8), and the presenilin-2 (PS-2) gene on chromosome 1 (9, 10). The majority of familial Alzheimer's disease cases are associated with over 40 independent mutations in the PS-1 genes of unrelated families that all display an early-ageof-onset Alzheimer's phenotype (8,(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Although the current literature suggests that intracellular PS-1 is intimately associated with the ␥-secretase activity that facilitates amyloid-␤ peptide release (26), the precise function of PS-1 proteins found in the synaptic membranes remains elusive and is also a matter of active investigation. Human PS-1 is widely expressed in a variety of organs throughout the body (8). This distribution raises the question as to why mutations in the PS-1 gene and its products appear to confer a disease state that selectively affects the brains of patients with familial Alzheimer's disease without apparent effect on their peripheral organs. In contrast, rat PS-1 is poorly expressed in liver, kidney, lung, and heart (27), and mouse PS-1 is poorly expressed in skeletal muscle and spleen. 2 We also reported that the PS-1 promoter was more active in cells differentiated to become neurons than in cells differentiated to a muscle phenotype (28). These differences suggest both cell type-specific and species-specific distributions of PS-1 expression. The brain, however, is the only organ where PS-1 is universally well expressed in human, rat, and mouse species. Using in situ hybridization, PS-1 mRNA is most highly expressed in neurons and below the limit of detection in other brain cells (29,30). These results strongly suggest the existence of a mechanism where PS-1 transcription is regulated in a neuron-specific manner in the brain.To understand presenilin-1 function, one of our approaches is to study regulatory mechanisms in the brain. PS-1 expression is higher in the hippocampus and cerebellum than in the cerebral cortex (29 -32). Hippocampal pyramidal neurons, dentate granule neurons, cerebellar Purkinje neurons, and primary olfactory cortical neurons show higher PS-1 expression than the neurons in other cortical regions of rat brain (33,34). Compared with the adult, the level of PS-1 expression is significantly higher in the developing rat brain. Peaking at postnatal day 10, PS-1 expression in the hippocampus and cerebellum is greatest at a time when proliferation, migration, and synapse formation are actively being completed (35).

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“…Our results clearly show lower levels of processed PS1 in the soluble fractions of brains that were obtained Using immunohistochemistry (IHC) and the CTF PS1 antibody, we further compared the PS1 levels in brains of CyPB KO animals and of their wild-type counterparts. Since PS1 is highly expressed in the hippocampus (Quarteronet et al, 1996), we focused on this brain structure and visualized the dentate gyrus (DG). The levels of PS1 in the DG of CyPB KO animals were remarkably lower than those seen in DG of wild-type animals (Figs 8E and EV5A).…”

Section: Reduced Quantities and Elevated Ps1 Aggregation In Brains Of...mentioning

confidence: 99%

Alzheimer's disease‐causing proline substitutions lead to presenilin 1 aggregation and malfunction

et al. 2015

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Do different neurodegenerative maladies emanate from the failure of a mutual protein folding mechanism? We have addressed this question by comparing mutational patterns that are linked to the manifestation of distinct neurodegenerative disorders and identified similar neurodegeneration-linked proline substitutions in the prion protein and in presenilin 1 that underlie the development of a prion disorder and of familial Alzheimer's disease (fAD), respectively. These substitutions were found to prevent the endoplasmic reticulum (ER)-resident chaperone, cyclophilin B, from assisting presenilin 1 to fold properly, leading to its aggregation, deposition in the ER, reduction of c-secretase activity, and impaired mitochondrial distribution and function. Similarly, reduced quantities of the processed, active presenilin 1 were observed in brains of cyclophilin B knockout mice. These discoveries imply that reduced cyclophilin activity contributes to the development of distinct neurodegenerative disorders, propose a novel mechanism for the development of certain fAD cases, and support the emerging theme that this disorder can stem from aberrant presenilin 1 function. This study also points at ER chaperones as targets for the development of counter-neurodegeneration therapies.

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Localization of presenilin-1 mRNA in rat brain

Cited by 15 publications

References 0 publications

Activation of transcription of the human presenilin 1 gene by 12‐O‐tetradecanoylphorbol 13‐acetate

Activation of transcription of the human presenilin 1 gene by 12‐O‐tetradecanoylphorbol 13‐acetate

Activated cAMP-response Element-binding Protein Regulates Neuronal Expression of Presenilin-1

Alzheimer's disease‐causing proline substitutions lead to presenilin 1 aggregation and malfunction

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