Publications related to Gamma secretase

Resistance mechanism to Notch inhibition and combination therapy in human T cell acute lymphoblastic leukemia

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy caused by acquisition of genetic alterations during T-cell development. The 5-year overall survival of pediatric T-ALL patients has improved considerably over the past 30 ...

EPFL2023

Prominent astrocytic alpha-synuclein pathology with unique post-translational modification signatures unveiled across Lewy body disorders

Hilal Lashuel, Melek Firat Altay

Alpha-synuclein (aSyn) is a pre-synaptic monomeric protein that can form aggregates in neurons in Parkinson's disease (PD), Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB), and in oligodendrocytes in multiple system atrophy (MSA ...

BMC2022

Capturing the heterogeneity of alpha-synuclein pathology in synucleinopathies

Melek Firat Altay

Synucleinopathies such as Parkinson's disease, dementia with Lewy bodies and multiple system atrophy (MSA) are detrimental neurodegenerative diseases. Alpha-synuclein (aSyn), the main aggregating protein found in the pathological inclusions of these ailmen ...

EPFL2022

Molecular dissection of amyloid disaggregation by human HSP70

Paolo De Los Rios, Alessandro Barducci

The molecular steps that lead to the disaggregation of amyloid fibrils are shown to involve the synergistic action of HSP70 and its co-chaperones DNAJB1 and HSP110. ...

NATURE RESEARCH2020

Zinc and Copper Differentially Modulate Amyloid Precursor Protein Processing by -Secretase and Amyloid- Peptide Production

Patrick Fraering, Mitko Dimitrov, Hermeto Gerber, Guillermo Miguel Garcia Osuna

Recent evidence suggests involvement of biometal homeostasis in the pathological mechanisms in Alzheimer's disease (AD). For example, increased intracellular copper or zinc has been linked to a reduction in secreted levels of the AD-causing amyloid- peptid ...

Amer Soc Biochemistry Molecular Biology Inc2017

Human Kunitz-type protease inhibitor engineered for enhanced matrix retention extends longevity of fibrin biomaterials

Jeffrey Alan Hubbell, Peter Frey, Hans Mattias Larsson, Priscilla Suhasna Maithili Briquez, Kristen Lorentz

Aprotinin is a broad-spectrum serine protease inhibitor used in the clinic as an anti-fibrinolytic agent in fibrin-based tissue sealants. However, upon re-exposure, some patients suffer from hypersensitivity immune reactions likely related to the bovine or ...

2017

Regulated intramembrane proteolysis of the AXL receptor kinase generates an intracellular domain that localizes in the nucleus of cancer cells

Patrick Fraering

Deregulation of the TAM (TYRO3, AXL, and MERTK) family of receptor tyrosine kinases (RTKs) has recently been demonstrated to predominately promote survival and chemoresistance of cancer cells. Intramembrane proteolysis mediated by presenilin/gamma-secretas ...

Federation Amer Soc Exp Biol2017

Studying membrane-protein interplay by modeling realistic conditions

Martina Audagnotto

Realistic models of cellular environments have long captured the imagination of biologists and physical scientists. More than 20 years ago, Goodshellâ s inspiring rendering of cellular environments provided the foundation for the idea of capturing the ful ...

EPFL2017

The lipidome associated with the gamma-secretase complex is required for its integrity and activity

Henning Paul-Julius Stahlberg, Patrick Fraering, Hermeto Gerber, Guillermo Miguel Garcia Osuna

gamma-Secretase is a multi-subunit membrane protease complex that catalyses the final intramembrane cleavage of the beta-amyloid precursor protein (APP) during the neuronal production of amyloid-beta peptides (A beta), which are implicated as the causative ...

Portland Press Ltd2016

Endogenous Regulators of Gamma-Secretase and Amyloid-Beta Production, and Engineering of Alzheimer's Disease Therapeutic Tools

Sébastien Mosser

Alzheimer s disease (AD) is a devastating neurodegenerative disease characterized by strong cognitive impairment and memory loss. These symptoms are caused by neuronal death, induced by two pathological hallmarks: extracellular senile plaques composed of a ...

EPFL2016

Proteolytic processing of the synaptic cell adhesion molecule neurexin-3beta and the neurobiological functions of the resulting cleavage products

Magda Maria Palczynska

Neurexins are key synaptic cell adhesion molecules involved in synapse specification and maturation. They couple synaptic activity and cell adhesion to regulate activity-dependent synapse development. Recently, neurexin processing by alpha- and gamma- secr ...

EPFL2016

Inhibition of Notch pathway arrests PTEN-deficient advanced prostate cancer by triggering p27-driven cellular senescence

Patrick Fraering, Mitko Dimitrov, Hermeto Gerber, Maria Luna Perciato, Jingjing Chen, Andrea Rinaldi

Activation of NOTCH signalling is associated with advanced prostate cancer and treatment resistance in prostate cancer patients. However, the mechanism that drives NOTCH activation in prostate cancer remains still elusive. Moreover, preclinical evidence of ...

Nature Publishing Group2016

Identification of new Presenilin-1 phosphosites: implication for gamma-secretase activity and A beta production

Patrick Fraering, Romain Hamelin, Mitko Dimitrov, Marc Moniatte, Sébastien Mosser, Alexandre Matz, Blanka Halamoda

An important pathological hallmark of Alzheimer's disease (AD) is the deposition of amyloid-beta (A) peptides in the brain parenchyma, leading to neuronal death and impaired learning and memory. The protease -secretase is responsible for the intramembrane ...

Wiley-Blackwell2015

Production of active glycosylation-deficient gamma-secretase complex for crystallization studies

Florian Maria Wurm, David Hacker, Patrick Fraering, Virginie Sandra Braman, Mitko Dimitrov, Hermeto Gerber, Andres Ricardo Lopez Robles

Alzheimer's disease (AD)-associated gamma-secretase is a ubiquitously expressed multi-subunit protease complex embedded in the lipid bilayer of cellular compartments including endosomes and the plasma membrane. Although gamma-secretase is of crucial intere ...

Wiley-Blackwell2015

The FDA-approved natural product dihydroergocristine reduces the production of the Alzheimer's disease amyloid-beta peptides

Patrick Fraering, Jianhua Liu, Jing Yu

Known gamma-secretase inhibitors or modulators display an undesirable pharmacokinetic profile and toxicity and have therefore not been successful in clinical trials for Alzheimer's disease (AD). So far, no compounds from natural products have been identifi ...

Nature Publishing Group2015

The adipocyte differentiation protein APMAP is an endogenous suppressor of Aβ production in the brain

Bernard Schneider, Patrick Fraering, Mitko Dimitrov, Sébastien Mosser, Justine Pascual, Alexandre Matz

The deposition of amyloid-beta (Aβ) aggregates in the brain is a major pathological hallmark of Alzheimer's disease (AD). Aβ is generated from the cleavage of C-terminal fragments of the amyloid precursor protein (APP-CTFs) by γ-secretase, an intramembrane ...

Oxford University Press2015

Structural differences of amyloid-beta fibrils revealed by antibodies from phage display

Hilal Lashuel, Patrick Droste

Background: Beside neurofibrillary tangles, amyloid plaques are the major histological hallmarks of Alzheimer's disease (AD) being composed of aggregated fibrils of beta-amyloid (A beta). During the underlying fibrillogenic pathway, starting from a surplus ...

Biomed Central Ltd2015

Inactivation of brain Cofilin-1 by age, Alzheimer's disease and gamma-secretase

Patrick Fraering, Sébastien Mosser, Eugenio Barone

Rapid remodeling of the actin cytoskeleton in the pre- and/or post-synaptic compartments is responsible for the regulation of neuronal plasticity, which is an important process for learning and memory. Cofilin1 plays an essential role in these processes an ...

Elsevier Science Bv2014

Perturbations of the Straight Transmembrane alpha-Helical Structure of the Amyloid Precursor Protein Affect Its Processing by gamma-Secretase

Matteo Dal Peraro, Patrick Fraering, Mitko Dimitrov, Thomas Lemmin

Background: Amyloid- neurotoxicity depends on the specificity of the proteolytic cleavage of the amyloid precursor protein (APP) transmembrane domain. Results: The APP transmembrane -helix is straight in a biological membrane bilayer. Conclusion: The flexi ...

American Society for Biochemistry and Molecular Biology2014

The Role of γ-Secretase Activating Protein (GSAP) and Imatinib in the Regulation of γ-Secretase Activity and Amyloid-β Generation

Valérie Eligert, Patrick Fraering, Mitko Dimitrov

gamma-Secretase is a large enzyme complex comprising presenilin, nicastrin, presenilin enhancer 2, and anterior pharynx-defective 1 that mediates the intramembrane proteolysis of a large number of proteins including amyloid precursor protein and Notch. Rec ...

2013