Gamma secretase

Résumé

Gamma secretase is a multi-subunit protease complex, itself an integral membrane protein, that cleaves single-pass transmembrane proteins at residues within the transmembrane domain. Proteases of this type are known as intramembrane proteases. The most well-known substrate of gamma secretase is amyloid precursor protein, a large integral membrane protein that, when cleaved by both gamma and beta secretase, produces a short 37-43 amino acid peptide called amyloid beta whose abnormally folded fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease patients. Gamma secretase is also critical in the related processing of several other type I integral membrane proteins, such as Notch, ErbB4, E-cadherin, N-cadherin, ephrin-B2, or CD44. Subunits and assembly The gamma secretase complex consists of four individual proteins: PSEN1 (presenilin-1), nicastrin, APH-1 (anterior pharynx-defective 1), and PEN-2 (presenilin enhancer 2). Recent evid

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La protéine précurseur de l'amyloïde (APP en anglais pour amyloid precursor protein) est une glycoprotéine transmembranaire de type I appartenant à la famille APP qui rassemble chez les mammifères,

Le peptide amyloïde bêta ou β-amyloïde est un peptide (une petite protéine) appartenant à la famille des substances amyloïdes. Dans certaines circonstances, il est néfaste pour le système nerveux ce

vignette|N1 dll4 cells. La voie de signalisation Notch est une cascade de signalisation conservée chez tous les métazoaires. Elle doit son nom au gène Notch, qui code le premier élément de la cascade,

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Biochemistry is a key discipline for the Life Sciences. Biological Chemistry I and II are two tightly interconnected courses that aim to describe and understand in molecular terms the processes that make life possible.

The course starts with fundamentals of electrical - and chemical signaling in neurons. Students then learn how neurons in the brain receive and process sensory information, and how other neurons control the behavior of an animal. Furthermore, memory, learning, and brain disorders will be introduced.

The goal of the course is to guide students through the essential aspects of molecular neuroscience and neurodegenerative diseases. The student will gain the ability to dissect the molecular basis of disease in the nervous system in order to begin to understand and identify therapeutic strategies.

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, , ,

Neurexins (NRXNs) are synaptic cell adhesion molecules having essential roles in the assembly and maturation of synapses into fully functional units. Immunocytochemical and electrophysiological studies have shown that specific binding across the synaptic cleft of the ectodomains of presynaptic NRXNs and postsynaptic neuroligins have the potential to bidirectionally coordinate and trigger synapse formation. Moreover, in vivo studies as well as genome-wide association studies pointed out implication of NRXNs in the pathogenesis of cognitive disorders including autism spectrum disorders and different types of addictions including opioid and alcohol dependences, suggesting an important role in synaptic function. Despite extensive investigations, the mechanisms by which NRXNs modulate the properties of synapses remain largely unknown. We report here that α- and γ-secretases can sequentially process NRXN3β, leading to the formation of two final products, an ∼80-kDa N-terminal extracellular domain of Neurexin-3β (sNRXN3β) and an ∼12-kDa C-terminal intracellular NRXN3β domain (NRXN3β-ICD), both of them being potentially implicated in the regulation of NRXNs and neuroligins functions at the synapses or in yet unidentified signal transduction pathways. We further report that this processing is altered by several PS1 mutations in the catalytic subunit of the γ-secretase that cause early-onset familial Alzheimer disease.

American Society for Biochemistry and Molecular Biology2010

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The causes of sporadic Alzheimer's Disease (AD), the most common form of dementia at old age, are still unknown. Familial early onset AD (FAD) is mainly caused by mutations of Presenilins (PS), the active subunits of γ-secretase. Processing of its substrate proteins by γ-secretase generates shorter fragments. In the case of the Amyloid Precursor Protein (APP) these are Aβ species, of which the ratio of Aβ40, which is 40 amino acids (aa) long and Aβ42, 42 aa in length respectively, has been connected with their aggregation and AD plaque formation. Another cleavage product of many γ-secretase substrate proteins are intracellular domains (ICDs), which enter the nucleus and alter gene transcription. Be it via statins, the levels of cAMP, the generation of which is also catalyzed by cilia specific Adenylyl-cyclase III (ACIII) or Wnt pathways, cilia can be connected with various AD relevant proteins, pathways and functions, but their physiological and thus pathological cerebral roles are not understood. We hypothesized that γ-secretase activity alterations impact transcription levels of specific genes and potentially signaling and functional pathways as well as cilia genes in ways relevant to AD. We determined the transcriptional impact of enhanced γ-secretase activity in Chinese hamster ovary (CHO) cells with a cDNA microarray experiment. Gene ontology cluster analysis of the 1981 genes reported by our microarray gave insights into functional groups represented. Matching of known physical protein-protein interactions as reported by the string 8.0 database for 21 genes, which were confirmed to be transcriptionally altered with γ-secretase activity, registered various members of three different Wnt pathways. Consistent with an hypothesized role of cilia, the array also reported two dozen of cilia-related genes. The most decreased transcript levels were of Anti-mitotic exit network homolog 1 (AMN1), a gene of predicted expression in the cilia of sensory olfactory neurons and for which protein data was available in yeast only. Our immunohistochemistry results confirm Amn1 protein expression in mammalian cells, specifically in murine and human brains. We showed that Amn1 protein is localized in cortical neurons and in sharply outlined intracellular structures close to motile cilia and the opposing cell pole of monocilia. Aged APPPS1 transgenic mice, which over express human APP and PS1 with FAD mutations, did neither show differences in lateral ventricular cilia range, cilia density, the percentage of ciliated hippocampal neurons nor ACIII protein levels. Consistently with previous reports of increased cAMP levels in the cerebrospinal fluid of AD patients, we detected significantly increased levels of ACIII protein in human AD cortex samples (AD n=11, non demented n=12). These results support a new focus on the role of cilia-related proteins in AD. They also suggest some limitations of the APPPS1 transgenic animal model. In recent years the impact and role of cilia-related proteins in various neurodegenerative diseases was demonstrated. This PhD thesis provides evidence that AD should be included in the list of neurodegenerative diseases which are being investigated for the impact and role of cilia-related proteins in their pathologies.

EPFL2011

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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 the therapeutic efficacy of NOTCH inhibitors in prostate cancer is lacking. Here, we provide evidence that PTEN loss in prostate tumours upregulates the expression of ADAM17, thereby activating NOTCH signalling. Using prostate conditional inactivation of both Pten and Notch1 along with preclinical trials carried out in Pten-null prostate conditional mouse models, we demonstrate that Pten-deficient prostate tumours are addicted to the NOTCH signalling. Importantly, we find that pharmacological inhibition of gamma-secretase promotes growth arrest in both Pten-null and Pten/Trp53-null prostate tumours by triggering cellular senescence. Altogether, our findings describe a novel pro-tumorigenic network that links PTEN loss to ADAM17 and NOTCH signalling, thus providing the rational for the use of gamma-secretase inhibitors in advanced prostate cancer patients.

Nature Publishing Group2016

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EPFL2011