APLP1 is endoproteolytically cleaved by γ-secretase without previous ectodomain shedding

Schauenburg, Linda; Liebsch, Filip; Eravci, Murat; Mayer, Magnus C.; Weise, Christoph; Multhaup, Gerhard

doi:10.1038/s41598-018-19530-8

Cited by 28 publications

(25 citation statements)

References 67 publications

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“…Laurent et al (2015), Schauenburg et al (2018) Family members with known shedding function are indicated in bold and italics. Selected review articles are given that typically describe the whole protease family.…”

Section: Plasma Membrane Endosomesmentioning

confidence: 99%

Proteolytic ectodomain shedding of membrane proteins in mammals—hardware, concepts, and recent developments

2018

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Proteolytic removal of membrane protein ectodomains (ectodomain shedding) is a post-translational modification that controls levels and function of hundreds of membrane proteins. The contributing proteases, referred to as sheddases, act as important molecular switches in processes ranging from signaling to cell adhesion. When deregulated, ectodomain shedding is linked to pathologies such as inflammation and Alzheimer's disease. While proteases of the "a disintegrin and metalloprotease" (ADAM) and "beta-site APP cleaving enzyme" (BACE) families are widely considered as sheddases, in recent years a much broader range of proteases, including intramembrane and soluble proteases, were shown to catalyze similar cleavage reactions. This review demonstrates that shedding is a fundamental process in cell biology and discusses the current understanding of sheddases and their substrates, molecular mechanisms and cellular localizations, as well as physiological functions of protein ectodomain shedding. Moreover, we provide an operational definition of shedding and highlight recent conceptual advances in the field. While new developments in proteomics facilitate substrate discovery, we expect that shedding is not a rare exception, but rather the rule for many membrane proteins, and that many more interesting shedding functions await discovery.

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Section: Plasma Membrane Endosomesmentioning

confidence: 99%

Proteolytic ectodomain shedding of membrane proteins in mammals—hardware, concepts, and recent developments

2018

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“…The Amyloid-like protein 1 (APLP1), a member of the APP family, was found to consistently decrease in 3 independent studies. This neuron-specific protein [69] is involved in the maintenance of dendritic spines and basal synaptic transmission [70]. APLP1 is a γ-secretase substrate [71], thereby, secreted APLP1 fragments might be of especial interest to investigate γ-secretase cleavage products in AD.…”

Section: Proteins Consistently Reduced In Ad Csfmentioning

confidence: 99%

A comprehensive systematic review of CSF proteins and peptides that define Alzheimer’s disease

et al. 2020

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Background: During the last two decades, over 100 proteomics studies have identified a variety of potential biomarkers in CSF of Alzheimer's (AD) patients. Although several reviews have proposed specific biomarkers, to date, the statistical relevance of these proteins has not been investigated and no peptidomic analyses have been generated on the basis of specific up-or down-regulation. Herein, we perform an analysis of all unbiased explorative proteomics studies of CSF biomarkers in AD to critically evaluate whether proteins and peptides identified in each study are consistent in distribution; direction change; and significance, which would strengthen their potential use in studies of AD pathology and progression. Methods: We generated a database containing all CSF proteins whose levels are known to be significantly altered in human AD from 47 independent, validated, proteomics studies. Using this database, which contains 2022 AD and 2562 control human samples, we examined whether each protein is consistently present on the basis of reliable statistical studies; and if so, whether it is over-or under-represented in AD. Additionally, we performed a direct analysis of available mass spectrometric data of these proteins to generate an AD CSF peptide database with 3221 peptides for further analysis. Results: Of the 162 proteins that were identified in 2 or more studies, we investigated their enrichment or depletion in AD CSF. This allowed us to identify 23 proteins which were increased and 50 proteins which were decreased in AD, some of which have never been revealed as consistent AD biomarkers (i.e. SPRC or MUC18). Regarding the analysis of the tryptic peptide database, we identified 87 peptides corresponding to 13 proteins as the most highly consistently altered peptides in AD. Analysis of tryptic peptide fingerprinting revealed specific peptides encoded by CH3L1, VGF, SCG2, PCSK1N, FBLN3 and APOC2 with the highest probability of detection in AD. Conclusions: Our study reveals a panel of 27 proteins and 21 peptides highly altered in AD with consistent statistical significance; this panel constitutes a potent tool for the classification and diagnosis of AD.

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“…Of course, of the three APP-related proteins, only APP itself can produce the Aβ peptide. Despite its close similarity to APP, the protein APLP1 apparently does not require cleavage by α- or β-secretase in order to be cleaved by γ-secretase ( Schauenburg et al, 2018 ). However, both APLP1 ( Li and Sudhof, 2004 ) and APLP2 ( Pastorino et al, 2004 ) can be cleaved by β-secretase ( Pastorino et al, 2004 ), and Aβ-equivalent peptides have been detected for these proteins ( Eggert et al, 2004 ; Yanagida et al, 2009 ) although there is little to suggest that these peptides have pathological activity.…”

Section: An Alternative Link Between Eofad-associated Mutations In Apmentioning

confidence: 99%

Dysregulation of Neuronal Iron Homeostasis as an Alternative Unifying Effect of Mutations Causing Familial Alzheimer’s Disease

et al. 2018

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The overwhelming majority of dominant mutations causing early onset familial Alzheimer’s disease (EOfAD) occur in only three genes, PSEN1, PSEN2, and APP. An effect-in-common of these mutations is alteration of production of the APP-derived peptide, amyloid β (Aβ). It is this key fact that underlies the authority of the Amyloid Hypothesis that has informed Alzheimer’s disease research for over two decades. Any challenge to this authority must offer an alternative explanation for the relationship between the PSEN genes and APP. In this paper, we explore one possible alternative relationship – the dysregulation of cellular iron homeostasis as a common effect of EOfAD mutations in these genes. This idea is attractive since it provides clear connections between EOfAD mutations and major characteristics of Alzheimer’s disease such as dysfunctional mitochondria, vascular risk factors/hypoxia, energy metabolism, and inflammation. We combine our ideas with observations by others to describe a “Stress Threshold Change of State” model of Alzheimer’s disease that may begin to explain the existence of both EOfAD and late onset sporadic (LOsAD) forms of the disease. Directing research to investigate the role of dysregulation of iron homeostasis in EOfAD may be a profitable way forward in our struggle to understand this form of dementia.

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APLP1 is endoproteolytically cleaved by γ-secretase without previous ectodomain shedding

Cited by 28 publications

References 67 publications

Proteolytic ectodomain shedding of membrane proteins in mammals—hardware, concepts, and recent developments

Proteolytic ectodomain shedding of membrane proteins in mammals—hardware, concepts, and recent developments

A comprehensive systematic review of CSF proteins and peptides that define Alzheimer’s disease

Dysregulation of Neuronal Iron Homeostasis as an Alternative Unifying Effect of Mutations Causing Familial Alzheimer’s Disease

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