Aβ Induces Excitotoxicity Mediated by APC/C-Cdh1 Depletion That Can Be Prevented by Glutaminase Inhibition Promoting Neuronal Survival

Fuchsberger, Tanja; Martínez-Bellver, Sergio; Giraldo, Esther; Teruel‐Martí, Vicent; Lloret, Ana; Viña, José

doi:10.1038/srep31158

Cited by 40 publications

(49 citation statements)

References 48 publications

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“…Interestingly, growing evidence suggests that dysregulation of APC/C-Cdh1 is involved in neurodegenerative diseases, potentially as a consequence of amyloid-ß driven proteasome-dependent degradation of CDH1 [50]. On the other hand, significantly higher methylation level of CDH1, inducing its inactivation, plays an important role in lung cancer [51].…”

Section: New Biological Insights On the Inverse Comorbidity Between Amentioning

confidence: 99%

Molecular Inverse Comorbidity between Alzheimer’s disease and Lung Cancer: new insights from Matrix Factorization

Greco

Valle

Pancaldi

et al. 2019

Preprint

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Matrix Factorization (MF) is an established paradigm for large-scale biological data analysis with tremendous potential in computational biology.We here challenge MF in depicting the molecular bases of epidemiologically described Disease-Disease (DD) relationships. As use case, we focus on the inverse comorbidity association between Alzheimer's disease (AD) and lung cancer (LC), described as a lower than expected probability of developing LC in AD patients. To the day, the molecular mechanisms underlying DD relationships remain poorly explained and their better characterization might offer unprecedented clinical opportunities.To this goal, we extend our previously designed MF-based framework for the molecular characterization of DD relationships. Considering AD-LC inverse comorbidity as a case study, we highlight multiple molecular mechanisms, among which the previously identified immune system and mitochondrial metabolism. We then discriminate mechanisms specific to LC from those shared with other cancers through a pancancer analysis. Additionally, new candidate molecular players, such as Estrogen Receptor (ER), CDH1 and HDAC, are pinpointed as factors that might underlie the inverse relationship, opening the way to new investigations. Finally, some lung cancer subtype-specific factors are also detected, suggesting the existence of heterogeneity across patients also in the context of inverse comorbidity.

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Section: New Biological Insights On the Inverse Comorbidity Between Amentioning

confidence: 99%

Molecular Inverse Comorbidity between Alzheimer’s disease and Lung Cancer: new insights from Matrix Factorization

Greco

Valle

Pancaldi

et al. 2019

Preprint

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“…More interesting is that Aβ inhibits cdh-1, depresses APC activity inducing rising levels of glutaminase and increases glutamate levels expressing thus exicitotoxicity in AD. This mediated excitotoxicity was found to be regulated through Cdh-1 [48]. Cdh 1 is primarily in a non phosphyrated form found in the nucleus.…”

Section: +mentioning

confidence: 99%

“…Recent finding by T. Fuchsberger [48] that Aβ with APC/C mediates excitotoxicity through the glutaminase pathway showed that this protein not only exerts properties for the late phases of the cell cycle but also properties for the maintenance of the postmitotic state through repressing cyclin B activity which suggest that APC/C has an important role in the pathogenesis of Alzheimer's disease. Glutamate is the most abundant neurotransmitter in the brain, with a wide range of functions.…”

Section: Introductionmentioning

confidence: 99%

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Late phase cell cycle proteins in Alzheimer’s disease: a possible target for therapy?

Bajić¹,

Bajić²,

Živković³

et al. 2016

J Syst Integr Neurosci

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Alzheimer's disease (AD) is represented by neuronal loss and this loss is correlated to a constant state of neuronal instability induced by intrinsic and extrinsic factors. In this paper data is presented regarding the possible roles of late phase cell cycle proteins in normal and affected neurons with the goal that understanding the mechanisms involved in the regulation of these proteins may represent a novel strategy for AD treatment. The results demonstrate a relative differential pattern of expression of certain proteins (APC/C, Mad1 and Mad2, Bub R1, Bub1, CDK 11, cohesin subunit Rad 21 and astrin) in the AD brain versus age matched controls, and it is suggested that targeting these proteins might translate into potential treatments for AD. Although the data presented here is of some interest, the ability to translate such information into clinical applications is often a challenge.

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“…Moreover, it has been reported recently that Aβ causes a proteasome-dependent degradation of cdh1 [21], suggesting its involvement in Alzheimer’s disease (AD).…”

Section: Introductionmentioning

confidence: 99%

New Functions of APC/C Ubiquitin Ligase in the Nervous System and Its Role in Alzheimer’s Disease

Fuchsberger

Lloret

Viña

2017

IJMS

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The E3 ubiquitin ligase Anaphase Promoting Complex/Cyclosome (APC/C) regulates important processes in cells, such as the cell cycle, by targeting a set of substrates for degradation. In the last decade, APC/C has been related to several major functions in the nervous system, including axon guidance, synaptic plasticity, neurogenesis, and neuronal survival. Interestingly, some of the identified APC/C substrates have been related to neurodegenerative diseases. There is an accumulation of some degradation targets of APC/C in Alzheimer’s disease (AD) brains, which suggests a dysregulation of the protein complex in the disorder. Moreover, recently evidence has been provided for an inactivation of APC/C in AD. It has been shown that oligomers of the AD-related peptide, Aβ, induce degradation of the APC/C activator subunit cdh1, in vitro in neurons in culture and in vivo in the mouse hippocampus. Furthermore, in the AD mouse model APP/PS1, lower cdh1 levels were observed in pyramidal neurons in CA1 when compared to age-matched wildtype mice. In this review, we provide a complete list of APC/C substrates that are involved in the nervous system and we discuss their functions. We also summarize recent studies that show neurobiological effects in cdh1 knockout mouse models. Finally, we discuss the role of APC/C in the pathophysiology of AD.

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Aβ Induces Excitotoxicity Mediated by APC/C-Cdh1 Depletion That Can Be Prevented by Glutaminase Inhibition Promoting Neuronal Survival

Cited by 40 publications

References 48 publications

Molecular Inverse Comorbidity between Alzheimer’s disease and Lung Cancer: new insights from Matrix Factorization

Molecular Inverse Comorbidity between Alzheimer’s disease and Lung Cancer: new insights from Matrix Factorization

Late phase cell cycle proteins in Alzheimer’s disease: a possible target for therapy?

New Functions of APC/C Ubiquitin Ligase in the Nervous System and Its Role in Alzheimer’s Disease

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