https://www.ncbi.nlm.nih.gov/gene/55851
NOTCH signaloinnin tärkeys tulee esiin jopa sokeritasapainossa.
Toisaalta taaas koko maailmaa kiinnostaa Abeeta amyloidinuodostus ja sen muodostuksen estäminen.
Gammasekretaasin geenin (PSENEN) tehtävä on koodata proteiineja, jotka säätelevät NOTCH signalointia ja myös prosessoida APP, joka on amyloidiprekursoriproteiini. Tästä jälkimmäsestä prosssoinnista kuitenkin jää jäljelle neurotoksista tuotetta Abeeta. Sen tuotantoa on koetettu vähentää muun muassa estämällä gamma-sekretaasia aktivoivaa proteiinia GSAP, jolloin on saatu Abeetan tuotantoa vähemmäksi.
Tässä mielestäni on jokin tasapainokartta NOTCH prosessoinnin ja APP prosessoinnin kesken.
on NOTCH signaalitie keuhkon pienten tiehyeiden epiteelistä.
https://www.atsjournals.org/doi/pdf/10.1164/rccm.200705-795OC
One such differentiation control system is the Notch signalingpathway. Originally discovered in Drosophila, there is evidence in experimental animals that the Notch pathway plays an important role in the determination of cell fate in multiple organsystems (7, 13, 15, 16) including the lung (7, 12–14). The classical role of Notch signaling is the prevention of cell differentiation and the maintenance of an undifferentiated state in stem cells in various organs (7, 15, 37). When Notch is ‘‘on,’’ differentiation is suppressed, whereas when Notch is ‘‘off,’’ cells are allowed to proceed to a specific differentiation fate (13, 15, 16). Notch typically acts locally to define boundaries between different cell types with divergent fates; for example, it can act following division of a stem cell to induce differentiation in one daughter cell and keep the other as a stem cell (13, 16).Notch signaling is simple in concept, but multiple regulatory components at every stage of the pathway add a level of complexity (13, 15–17). Notch signaling in humans is initiated by interaction of one of the five Notch ligands, Delta-like (DLL1,3, or 4) or Jagged (JAG1 or 2) with one of the four receptors (NOTCH1, 2, 3, or 4). Both ligand and receptor are single-pass membrane proteins, and therefore Notch signaling typically involves cell-to-cell contact. Ligand-receptor binding is followed by cleavage of the Notch receptor and release of the Notch intracellular domain (NICD). NICD is vulnerable to proteolysis by modulators such as Numb and Itch; if not proteolyzed, NICD translocates to the nucleus and displaces CBF1, a transcription factor, from an inhibitory complex. CBF1 then associates with a stimulatory complex including the Mastermind-like (MAML) protein. The stimulatory complex binds to a consensus sequence(RTGGGAA), resulting in transcription of a group of inhibitory transcription factors known as basic helix-loop-helix (bHLH)genes, including HES1, 2, and 5, and HEY1, 2, and L. In turn, thebHLH genes suppress the expression of downstream differentiation factors including ASCL1, UBE2A and MYOD. Therefore,when Notch signaling is ‘‘on,’’ bHLH genes are transcribed and suppress transcription of differentiation factors, maintaining‘‘stemness.’’ Conversely, when Notch signaling is ‘‘off,’’ bHLHgenes are not transcribed, permitting transcription of differenti-ation factors and differentiation to a specific cell fate.With this background, we asked two questions. First, are Notch-related genes being expressed in the adult human airway epithelial transcriptome, and if so, what are the relative expression levels of the Notch pathway ligands (Delta-like ligands, DLL1, 3, and 4; Jagged, JAG1 and 2), receptors (NOTCH1, 2, 3, and 4), and downstream effectors (HES1, 2, and 5; HEY1, 2, andL)? Second, based on the knowledge that cigarette smoking and its associated disorder chronic obstructive pulmonary disease (COPD) are characterized by abnormal patterns of differentiation of the airway epithelium, is the expression of genes in the Notch pathway modulated in normal smokers and smokers with COPD? To assess these questions, we first compiled a list of 55 genes related to the Notch pathway and used microarray technology to assess the expression of these genes in the epithelium of small airways of healthy nonsmokers. Notch proteins were also assessed by performing immunohistochemical analysis on large airway biopsy samples from a subset of the subjects and on brushed small airway epithelial cells from an independent set of subjects. Following this screen of expression of the Notch pathway, we used TaqMan quantitative polymerase chain reaction (PCR) to assess relative expression levels of the key Notch genes in the small airway epithelium of normal nonsmokers, normal smokers, and smokers with COPD. The data demonstrate that most of the genes in the Notch pathway are expressed in the adult human small airway epithelium, and that the expression levels of key genes in the pathway are affected by smoking, both in phenotypic normal smokers and smokers who have developed COPD, observations that are consistent with this pathway playing a role in repair and differentiation in the adult lung. Some of the results of these studies have been previously reported in the form of an abstract (18, 19).
Lisäksi APP omaa kylla mahdollisuuden prosessoitua siten, että siitä ei jää mitään toxista tuotetta ja siinä toimii kronologinen normaalijärjestys sekretaaseilla: alfa> beta> gamma > APP pilkkoutuu oikeista kohdista > pystyy katoamaan silppurissa.
Mitä siinä tapauksessa NOTCH säätelyssä tapahtuu ?
Ehkä on karttoja olemassa jossa molemmat säätelylinjat ja niiden välinen normaalitasapaino näkyy. Normaalia on että "roskista ei näy mitään" paitsi ehkä stabiili energiatasapaino ja painon vakaus.
Gamma- sekretaasigeeniå esiintyy yleisesti kehossa.
https://www.ncbi.nlm.nih.gov/gene/55851
Koetan ainakin katsoa E3 ligaaseista niitä, jotka vaikutavat NOTCH.in puolella, koska niitä pidettiin v 2004 tuntemattomina.
NOTCH omaa saman tapaisen domaanijärjestelmän kuin APP, jossa on tärkeää käsitellä pieni sisään jäävä ja transmebraaninen ja ulos solusta pistävä osa asianmukaisesti oikeista kohdista hajoittamalla, ihan kuin punkin irtiruuvaamisessa ettei jää osia aiheuttamaan ongelmia.
https://pubmed.ncbi.nlm.nih.gov/28096459/
2017 Mar 3;292(9):3751-3767.
Zinc and Copper Differentially Modulate Amyloid Precursor Protein Processing by γ-Secretase and Amyloid-β Peptide Production
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-β peptide (Aβ). However,
little is known about whether these biometals modulate the generation of
Aβ. In the present study we demonstrate in both cell-free and
cell-based assays that zinc and copper regulate Aβ production by
distinct molecular mechanisms affecting the processing by γ-secretase of
its Aβ precursor protein substrate APP-C99.
We found that Zn2+ induces APP-C99 dimerization, which prevents its cleavage by γ-secretase and Aβ production, with an IC50 value of 15 μm
Importantly, at this concentration, Zn2+ also drastically raised the production of the aggregation-prone Aβ43 found in the senile plaques of AD brains and elevated the Aβ43:Aβ40 ratio, a promising biomarker for neurotoxicity and AD.
We further demonstrate that the APP-C99 histidine residues His-6, His-13, and His-14 control the Zn2+-dependent APP-C99 dimerization and inhibition of Aβ production,
whereas the increased Aβ43:Aβ40 ratio is substrate dimerization-independent and involves the known Zn2+ binding lysine Lys-28 residue that orientates the APP-C99 transmembrane domain within the lipid bilayer.
Unlike zinc, copper inhibited Aβ production by directly targeting the subunits presenilin and nicastrin in the γ-secretase complex.
Altogether, our data demonstrate that zinc and copper differentially modulate Aβ production. They further suggest that dimerization of APP-C99 or the specific targeting of individual residues regulating the production of the long, toxic Aβ species, may offer two therapeutic strategies for preventing AD.
Keywords:
Alzheimer disease; amyloid precursor protein (APP); amyloid-β
(AB); biometals; copper; intramembrane proteolysis; neurodegeneration;
zinc.
We found that Zn2+ induces APP-C99 dimerization, which prevents its cleavage by γ-secretase and Aβ production, with an IC50 value of 15 μm
Importantly, at this concentration, Zn2+ also drastically raised the production of the aggregation-prone Aβ43 found in the senile plaques of AD brains and elevated the Aβ43:Aβ40 ratio, a promising biomarker for neurotoxicity and AD.
We further demonstrate that the APP-C99 histidine residues His-6, His-13, and His-14 control the Zn2+-dependent APP-C99 dimerization and inhibition of Aβ production,
whereas the increased Aβ43:Aβ40 ratio is substrate dimerization-independent and involves the known Zn2+ binding lysine Lys-28 residue that orientates the APP-C99 transmembrane domain within the lipid bilayer.
Unlike zinc, copper inhibited Aβ production by directly targeting the subunits presenilin and nicastrin in the γ-secretase complex.
Altogether, our data demonstrate that zinc and copper differentially modulate Aβ production. They further suggest that dimerization of APP-C99 or the specific targeting of individual residues regulating the production of the long, toxic Aβ species, may offer two therapeutic strategies for preventing AD.
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