Presenilin 1 Independently Regulates β-Catenin Stability and Transcriptional Activity

Killick, Richard; Pollard, Cleo; Asuni, Ayodeji A.; Mudher, Amritpal; Richardson, Jill C.; Rupniak, H. T.; Sheppard, Paul W.; Varndell, Ian M.; Brion, Jean Pierre; Levey, Aĺlan I.; Levy, Oren; Vestling, Monika; Cowburn, Richard F.; Lovestone, Simon; Anderton, Brian H.

doi:10.1074/jbc.m108332200

Cited by 41 publications

(28 citation statements)

References 50 publications

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“…␤-Catenin is constitutively degraded through sequential phosphorylation events promoted within at least two distinct molecular complexes. The major complex consists of axin and its associated proteins, and the second complex involves presenilin-1 (PS1) and PS2, the membrane proteins responsible for the intramembranous processing of the ␤-amyloid precursor protein in Alzheimer's disease (24,25,39,51,57). ␤-Catenin phosphorylation is inhibited by Wnt activation of frizzled/LRP receptors, leading to protein accumulation and translocation to the nucleus, where it activates TCF/LEF transcriptional complexes in the promoters of target genes.…”

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confidence: 99%

A Regulatory Circuit Mediating Convergence between Nurr1 Transcriptional Regulation and Wnt Signaling

Kitagawa

Ray

Glantschnig

et al. 2007

Molecular and Cellular Biology

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The orphan nuclear receptor Nurr1 is essential for the development and maintenance of midbrain dopaminergic neurons, the cells that degenerate during Parkinson's disease, by promoting the transcription of genes involved in dopaminergic neurotransmission. Since Nurr1 lacks a classical ligand-binding pocket, it is not clear which factors regulate its activity and how these factors are affected during disease pathogenesis. Since Wnt signaling via ␤-catenin promotes the differentiation of Nurr1؉ dopaminergic precursors in vitro, we tested for functional interactions between these systems. We found that ␤-catenin and Nurr1 functionally interact at multiple levels. In the absence of ␤-catenin, Nurr1 is associated with Lef-1 in corepressor complexes. ␤-Catenin binds Nurr1 and disrupts these corepressor complexes, leading to coactivator recruitment and induction of Wnt-and Nurr1-responsive genes. We then identified KCNIP4/calsenilin-like protein as being responsive to concurrent activation by Nurr1 and ␤-catenin. Since KCNIP4 interacts with presenilins, the Alzheimer's disease-associated proteins that promote ␤-catenin degradation, we tested the possibility that KCNIP4 induction regulates ␤-catenin signaling. KCNIP4 induction limited ␤-catenin activity in a presenilindependent manner, thereby serving as a negative feedback loop; furthermore, Nurr1 inhibition of ␤-catenin activity was absent in PS1 ؊/؊ cells or in the presence of small interfering RNAs specific to KCNIP4. These data describe regulatory convergence between Nurr1 and ␤-catenin, providing a mechanism by which Nurr1 could be regulated by Wnt signaling.Expression and maintenance of the dopaminergic phenotype in the ventral midbrain (VM) require the orphan nuclear receptor (NR) Nurr1 (NR4A2) (48,59). Genetic ablation of Nurr1 produces embryonic lethality due to a nearly complete absence specifically of mesencephalic dopaminergic neurons, which are critical for motor function. Nurr1 regulates both the differentiation and the maintenance of these dopaminergic cells, as Nurr1 ϩ/Ϫ mice appear normal at birth but develop motor deficits resulting from reduced numbers of dopaminergic neurons and lower dopamine levels in the striatum (22). At the molecular level, Nurr1 binds specific response elements in the promoters of genes involved in dopaminergic neurotransmission, such as the genes encoding tyrosine hydroxylase (TH), L-aromatic amino acid decarboxylase, and the dopamine transporter (20,26,44,45). In Parkinson's disease, mesencephalic dopaminergic neurons degenerate, ultimately leading to severe motor deficits; correspondingly, Nurr1 levels appear to be reduced (10, 11). Therapeutic strategies that promote Nurr1 function in Parkinson's disease might therefore restore dopaminergic function or even increase the number of dopaminergic neurons. However, Nurr1 has a closed ligand-binding pocket and thus appears to be regulated by ligand-independent mechanisms (55). These mechanisms include changes in the expression of its RNA and protein (36,47,54) and changes by seco...

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confidence: 99%

A Regulatory Circuit Mediating Convergence between Nurr1 Transcriptional Regulation and Wnt Signaling

Kitagawa

Ray

Glantschnig

et al. 2007

Molecular and Cellular Biology

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“…Interestingly, FADlinked mutations (M146L, ⌬exon9, C263R, and P246L) have been found to impair this ␥-secretase-independent activity as well, resulting in enhanced ␤-catenin stability and ␤-catenin-dependent signaling (26,27). Recently, PS holoproteins were found to function as passive ER calcium leak channels independent of ␥-secretase activity, and two FAD-associated mutations (PS1 M146V and PS2 N141L) impaired this function (28).…”

Section: Fad-linked Ps Mutations Impairmentioning

confidence: 99%

The presenilin hypothesis of Alzheimer's disease: Evidence for a loss-of-function pathogenic mechanism

Shen

Kelleher

2007

Proc. Natl. Acad. Sci. U.S.A.

431

358

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Dominantly inherited mutations in the genes encoding presenilins (PS) and the amyloid precursor protein (APP) are the major causes of familial Alzheimer's disease (AD). The prevailing view of AD pathogenesis posits that accumulation of ␤-amyloid (A␤) peptides, particularly A␤42, is the central event triggering neurodegeneration. Emerging evidence, however, suggests that loss of essential functions of PS could better explain dementia and neurodegeneration in AD. First, conditional inactivation of PS in the adult mouse brain causes progressive memory loss and neurodegeneration resembling AD, whereas mouse models based on overproduction of A␤ have failed to produce neurodegeneration. Second, whereas pathogenic PS mutations enhance A␤42 production, they typically reduce A␤40 generation and impair other PS-dependent activities. Third, ␥-secretase inhibitors can enhance the production of A␤42 while blocking other ␥-secretase activities, thus mimicking the effects of PS mutations. Finally, PS mutations have been identified in frontotemporal dementia, which lacks amyloid pathology. Based on these and other observations, we propose that partial loss of PS function may underlie memory impairment and neurodegeneration in the pathogenesis of AD. We also speculate that A␤42 may act primarily to antagonize PS-dependent functions, possibly by operating as an active site-directed inhibitor of ␥-secretase.A lzheimer's disease (AD) is an age-related neurodegenerative dementia and is the most common cause of both neurodegeneration and dementia. Neurodegenerative dementias are characterized clinically by progressive impairment of cognitive abilities, which most prominently affects memory in AD. Neuronal and synaptic loss is the essential neuropathological feature common to different forms of neurodegenerative dementias, including AD, frontotemporal dementia (FTD) and Lewy body dementia (LBD). These diseases are distinguished neuropathologically by characteristic patterns of abnormal protein aggregation, such as the presence in the AD brain of cerebral cortical amyloid plaques and neurofibrillary tangles (NFTs). Extracellular amyloid plaques consist primarily of 40-to 42-residue ␤-amyloid (A␤) peptides (A␤40 and A␤42) derived from proteolytic processing of the amyloid precursor protein (APP). NFTs are intraneuronal inclusions composed of hyperphosphorylated forms of the microtubule-associated protein tau.Research on AD has been greatly stimulated by the identification of causative mutations in the genes encoding APP and presenilins (PS1 and PS2). Dominantly inherited missense mutations in APP increase the production of A␤ peptides and account for Ϸ10% of mutations identified in familial AD (FAD). PSs harbor Ϸ90% of identified FAD mutations, and many of these mutations increase the relative production of A␤42 peptides. The prevailing amyloid hypothesis posits that accumulation of A␤ peptides, particularly the more hydrophobic and aggregation-prone A␤42, triggers a pathogenic cascade, leading to neurodegeneration in AD (1). However, a...

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“…PS-1 is a critical component of the ␥-secretase complex, and mutant PS-1 increases the production of amyloid peptides (10) as well as the proteolysis of Notch intracellular domain (11). PS-1 has also been shown to interact with members of the armadillo family of proteins, including ␤-catenin (12)(13)(14).…”

Section: Ps-1 Is Associated With Modulation Of Wnt͞␤-catenin Signalinmentioning

confidence: 99%

Specific inhibition of CBP/β-catenin interaction rescues defects in neuronal differentiation caused by a presenilin-1 mutation

Teo

Nguyen

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

152

133

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mutant, PS-1(L286V), causes a dramatic increase in T cell factor (TCF)͞␤-catenin transcription in PC-12 cells, which prevents normal nerve growth factor (NGF)-induced neuronal differentiation and neurite outgrowth. Selective inhibition of TCF͞␤-catenin͞cAMP-response elementbinding protein (CREB)-binding protein (CBP)-mediated transcrip-tion, but not TCF͞␤-catenin͞p300, with the recently described small molecule antagonist ICG-001 corrects these defects in neuronal differentiation, highlighting the importance of Wnt͞␤-catenin signaling in this process. We propose that increased TCF͞␤-catenin͞ CBP-mediated transcription, as well as a failure to switch to TCF͞␤-catenin͞p300-mediated transcription, play an important role in decreasing neuronal differentiation.Wnt͞␤-catenin ͉ Alzheimer's disease

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Presenilin 1 Independently Regulates β-Catenin Stability and Transcriptional Activity

Cited by 41 publications

References 50 publications

A Regulatory Circuit Mediating Convergence between Nurr1 Transcriptional Regulation and Wnt Signaling

A Regulatory Circuit Mediating Convergence between Nurr1 Transcriptional Regulation and Wnt Signaling

The presenilin hypothesis of Alzheimer's disease: Evidence for a loss-of-function pathogenic mechanism

Specific inhibition of CBP/β-catenin interaction rescues defects in neuronal differentiation caused by a presenilin-1 mutation

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