Modulation of Aβ generation by small ubiquitin-like modifiers does not require conjugation to target proteins

Dorval, Véronique; Mazzella, Matthew J.; Mathews, Paul M.; Hay, Ronald T.; Fraser, Paul E.

doi:10.1042/bj20061451

Cited by 63 publications

(58 citation statements)

References 41 publications

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“…For example, the transcription factor ETS2 is thought to transactivate the APP promoter, leading to overexpression 123 . The chromosome 21-encoded proteins small ubiquitin-related modifier 3 (SUMO3) and dualspecificity tyrosinephosphorylation-regulated kinase 1A (DYRK1A) modify APP posttranslationally, which may alter Aβ generation [124][125][126] . Additionally, the chromosome 21 microRNA miR-155 has been suggested to modulate γ-secretase activity and hence the processing of APP, through its effect on the expression of sorting nexin 27 (REF.…”

Section: Interaction Of Other Chromosome 21 Genes With Appmentioning

confidence: 99%

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

et al. 2015

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Down syndrome, which arises in individuals carrying an extra copy of chromosome 21, is associated with a greatly increased risk of early-onset Alzheimer disease. It is thought that this risk Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts is conferred by the presence of three copies of the gene encoding amyloid precursor protein (APP) -an Alzheimer disease risk factor -although the possession of extra copies of other chromosome 21 genes may also play a part. Further study of the mechanisms underlying the development of Alzheimer disease in people with Down syndrome could provide insights into the mechanisms that cause dementia in the general population.Down syndrome (DS) is a complex, highly variable disorder that arises from trisomy of chromosome 21. It was one of the first chromosomal disorders to be identified 1 and occurs with an incidence of approximately 1 in 800 births 2 . Its prevalence within a given population is influenced by infant mortality rates, access to health care, termination rates, average maternal age 3 and life expectancy. Indeed, despite the increased availability of prenatal diagnosis and access to the option of termination, the global prevalence of DS is rising because of improvements in life expectancy: the number of adults with DS aged over 40 years has doubled in northern Europe since 1990 and, in the United Kingdom, one-third of the estimated 40,000 people with DS are thought to be over 40 years of age 4 .DS is the most common form of intellectual disability. In addition to the features that are found in everyone with the disorder, such as the characteristic facial dysmorphology, there are many DS-associated phenotypes that have variable penetrance and severity. For example, approximately 40% of individuals with DS have heart malformations (usually atrioventricular septal defects) 5 . A key feature of DS is a striking propensity to develop early-onset Alzheimer disease (EOAD). Complete trisomy of chromosome 21 universally causes the development of amyloid plaques and neurofibrillary tangles (NFTs), which are typical characteristics of AD brain pathology, by the age of 40, and approximately twothirds of individuals with DS develop dementia by the age of 60 (REFS 6,7). However, rates of dementia do not reach 100%, even in older individuals, suggesting that some individuals with DS are protected from the onset of AD (FIG. 1).All of the features of DS arise because of aberrant dosages of coding and/or non-coding sequences present on chromosome 21. Among these sequences, the gene encoding amyloid precursor protein (APP) is thought to have a key role in the pathology of AD. The additional copy of APP may drive the development of AD in individuals with DS (AD-DS) by increasing the levels of amyloid-β (Aβ), a cleavage product of APP that misfolds and accumulates in the brain in people with AD. Consistent with this hypothesis, individuals with small internal chromosome 21 duplications that result in three copies of APP -a rare familial trait known as duplic...

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Section: Interaction Of Other Chromosome 21 Genes With Appmentioning

confidence: 99%

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

et al. 2015

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“…Using SUMO-3 conjugation and polymerizationdeficient mutants resulted in no differences in APP cleavage from the active, polymerizing form, suggesting that the effect is due to SUMO-3 monomers and is a noncovalent effect or that some compensation is occurring. A decrease in SUMOylated substrates was observed after SUMO knockdown by RNAi, but no parallel changes in the amyloidogenic processing of APP were observed suggesting endogenous SUMO was not an essential regulatory factor and played an indirect role in APP processing and production of Aβ [42]. In contrast with these observations, another study identified a ψKx(E/D) SUMOylation motif around lysines 587 and 595 of APP.…”

Section: App and Sumoylationmentioning

confidence: 45%

SUMOylation: Novel Neuroprotective Approach for Alzheimer’s Disease?

2015

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Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized in the brain by the formation of amyloid-beta (Aβ)-containing plaques and neurofibrillary tangles containing the microtubule-associated protein tau. Neuroinflammation is another feature of AD and astrocytes are receiving increasing attention as key contributors. Although some progress has been made, the molecular mechanisms underlying the pathophysiology of AD remain unclear. Interestingly, some of the main proteins involved in AD, including amyloid precursor protein (APP) and tau, have recently been shown to be SUMOylated. The post-translational modification by SUMO (small ubiquitin-like modifier) has been shown to regulate APP and tau and may modulate other proteins implicated in AD. Here we present an overview of recent studies suggesting that protein SUMOylation might be involved in the underlying pathogenic mechanisms of AD and discuss how this could be exploited for therapeutic intervention.

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“…L'inhibition de la dégradation des protéines par le protéasome augmente l'ubiquitinylation de Tau et diminue sa sumoylation [31], révélant l'existence d'une régulation fine entre ces deux modifications post-traductionnelles pour le maintien de la stabilité de Tau. Bien que les résultats soient controversés [33], la surexpression de SUMO-3 diminue dramatiquement la production du peptide Aβ impliquant ainsi directement la sumoylation dans la maladie d'Alzheimer [34].…”

Section: La Maladie D'alzheimerunclassified

Nouvelles fonctions extranucléaires de la sumoylation des protéines dans le système nerveux central

Martin

2009

Med Sci (Paris)

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La modification post-traductionnelle des protéines est un processus enzymatique qui consiste en l'ajout de groupements chimiques, de sucres, de lipides ou encore de polypeptides après la synthèse protéique. Ces modifications peuvent altérer la conformation des protéines, influer sur leur localisation cellulaire, dicter leur stabilité ou encore agir sur leur activité et donc sur leur fonction physiologique. Par exemple, les processus synaptiques de la communication neuronale sont particulièrement complexes et finement régulés, en partie grâce à ces modifications post-traductionnelles. La sumoylation est une modification post-traductionnelle dont les fonctions en dehors du noyau sont peu connues. Cette synthèse fait le point sur notre connaissance des fonctions extranucléaires de la sumoylation dans le système nerveux central et discute leur implication dans les maladies neurodégénératives. Qu'est-ce que la sumoylation ?La sumoylation a été découverte en 1996 [1]. C'est un processus enzymatique qui consiste en l'attachement covalent d'une protéine appelée SUMO (small ubiquitinlike modifier) sur la lysine de la séquence consensus ΨKxD/E d'une protéine cible (Ψ, acide aminé hydrophobe ; K, lysine modifiée ; x, résidu quelconque et D/E, aspartate ou glutamate). Il faut cependant noter que la littérature rapporte un nombre de plus en plus élevé de protéines sumoylées sur des lysines n'appartenant pas à un site consensus de sumoylation. Bien que la séquence primaire de SUMO soit différente de celle de l'ubiquitine, la structure tridimensionnelle de ces deux protéines est similaire (Figure 1). La sumoylation est un processus essentiel puisque l'invalidation des enzymes de la sumoylation est délétère pour les cellules eucaryotes [2,3]. Le terme SUMO regroupe une famille de 4 protéines (SUMO1-4), formées chacune d'environ 100 résidus. Les formes SUMO1-3 sont exprimées dans le cerveau alors que l'expression de SUMO-4 semble restreinte aux cellules des reins, de la rate et des ganglions lymphatiques. SUMO-2 et SUMO-3 ne diffèrent que par 3 résidus et ne présentent que 47 % d'homologie avec SUMO-1. De manière très intéressante, SUMO-2 et 3 peuvent former des chaînes de poly-SUMO, contrairement à SUMO-1 qui ne comporte pas le résidu de lysine indispensable à la formation de ces chaînes [4]. > Les modifications post-traductionnelles de protéines sont essentielles à la régulation de leur fonction et, par conséquent, au maintien de l'intégrité cellulaire. Ces modifications interviennent à tous les niveaux de la communication entre les neurones du système nerveux central. La sumoylation est une modification post-traductionnelle qui crée une liaison covalente entre une lysine de la protéine cible et une petite protéine appelée SUMO. C'est un processus réversible qui fait intervenir des enzymes spécifiques. La sumoylation est un processus régulateur fonctionnel bien connu de l'activité nucléaire et il est maintenant clairement établi que dans les neurones, il assure également un rôle majeur pour de nombreux processus extranucléai-r...

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Modulation of Aβ generation by small ubiquitin-like modifiers does not require conjugation to target proteins

Cited by 63 publications

References 41 publications

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

SUMOylation: Novel Neuroprotective Approach for Alzheimer’s Disease?

Nouvelles fonctions extranucléaires de la sumoylation des protéines dans le système nerveux central

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