Involvement of δ-secretase in neurodegenerative diseases (Homo sapiens)

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1, 2Amyloid-beta promotes δ-secretase expressionSET fragment: hyperphosphorylation -> tau aggregationvia PP2A inhibitionAggregationMore prone to aggregation-> neurotoxic effectCleaved SRPK2 increasesnuclear translocationand kinase activity -> promoting tau aggregationTDP-43: aggregationin inclusion bodiesTau (1-368) fragment:more prone to phosphorylationBlocked TrkB -> increased delta-secretase expression,fragmentation of APP and tau,blockage of neuronal signals ->neuronal cell deathPhosphorylated by SRPK2:promote enzymatic activityPhosphorylated by AKT:inhibit enzymatic activationα-synucleinAKT 2SETDOPALSRPK2 fragmentC/EBP10A𝛽BDNFBACE1AKT 1δ-secretaseα-synuclein (1-103) fragmentTDP-43Microtubule-associated protein tauPP2AMAO BLGMNδ-secretase SET fragmentPP2AAmyloid-betaAKT 3Tau (1-368) fragmentTDP-43 fragmentTrkBSTAT1Microtubule-associated protein tauAPPProlegumainAlzheimer's diseaseDopamineSRPK2APPAKT 1PAKT 2PAKT 3P


Description

Mammalian asparagine endopeptidase, also known as δ-secretase , is a key player in a number of neurodegenerative illnesses, including Alzheimer's, Parkinson's or ALS. The enzyme can get activated in the aging brain and starts to cleave amyloid precursor protein (APP) and promotes the production of amyloid-β (Aβ). δ-secretase also breaks down tau, alpha-synuclein, SET, and TAR DNA-binding protein 43, generating neurotoxic fragments and impairing their physiological processes. Each fragment has either been identified in patient samples with the relevant disease or has undergone testing to determine whether it can cause the disease pathology. This pathway is based on Figure 1 from the paper:"δ-secretase in neurodegenerative diseases: mechanisms, regulators and therapeutic opportunities. published by Zhang Z, Tian Y, Ye K.

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Ontology Terms

 

Bibliography

  1. Zhang Z, Tian Y, Ye K; ''δ-secretase in neurodegenerative diseases: mechanisms, regulators and therapeutic opportunities.''; Transl Neurodegener, 2020 PubMed Europe PMC Scholia
  2. Liu C, Götz J; ''How it all started: tau and protein phosphatase 2A.''; J Alzheimers Dis, 2013 PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
129533view01:28, 9 May 2024EweitzOntology Term : 'neuron' added !
128716view01:31, 21 February 2024EweitzOntology Term : 'neurodegenerative pathway' added !
128715view01:31, 21 February 2024EweitzOntology Term : 'amyotrophic lateral sclerosis pathway' added !
128714view23:11, 20 February 2024EweitzModified description
128713view23:09, 20 February 2024EweitzNote relation to Parkinson's disease, per source
128712view23:05, 20 February 2024EweitzNote relation to FTD and ALS, per source
128711view22:57, 20 February 2024EweitzNote relation to Alzheimer's disease, per source diagram
128710view22:53, 20 February 2024EweitzRefine interaction per source; refine metabolite name
128695view21:20, 19 February 2024EweitzRefine caption placement
128694view21:19, 19 February 2024EweitzFix typo, color metabolites blue, economize
126830view10:04, 26 June 2023Pat hoferchanged ID of phosphorylated delta-secretase
126826view19:39, 25 June 2023Pat hoferChanged arrows of phosphorylation-reactions to MIM-modification-interaction
126825view19:30, 25 June 2023Pat hoferChanged ID of delta-secretase, comments for prolegumain, added akt 1/2/3 as a group
126819view09:13, 25 June 2023Tamara FitzingerOntology Term : 'Parkinson's disease pathway' added !
126818view09:12, 25 June 2023Tamara FitzingerOntology Term : 'Alzheimer's disease pathway' added !
126779view13:44, 22 June 2023DeSlUpdated desription, removed comments with personal email details
126744view15:18, 16 June 2023Tamara FitzingerModified description
126743view15:04, 16 June 2023Pat hoferLiterature update
126741view14:27, 16 June 2023Pat hoferadded Prolegumain and Legumain
126740view14:02, 16 June 2023Marlenef97Modified description
126738view10:34, 16 June 2023Pat hofer
126737view09:05, 16 June 2023Pat hofer
126736view09:00, 16 June 2023Pat hofer
126735view08:56, 16 June 2023Pat hofer
126734view08:53, 16 June 2023Pat hoferchanged datasource of IDs, added PP2A, changed linestle of inhibition of tau phosphorylation
126716view12:13, 15 June 2023Pat hoferAdded IDs for Tau-protein and APP
126715view11:44, 15 June 2023Pat hofer
126714view11:41, 15 June 2023Pat hoferChanged Uniprot/Swiss IDs to Uniprot/Trembl IDs
126685view14:46, 12 June 2023Marlenef97
126669view07:46, 10 June 2023Pat hofer
126655view16:01, 9 June 2023Marlenef97- controlled all IDs

- located STAT1 and BACE1 in nucleus - changed interaction between amyloid-beta and sectretase to interaction between amyloid beta and LGMN - changed interaction of TrkB and C/EBP from mim-stimulation to mim-inhibition

- added comment
126640view11:14, 8 June 2023Pat hofer
126639view11:12, 8 June 2023Pat hofer
126638view10:55, 8 June 2023Pat hofer
126637view10:53, 8 June 2023Pat hofer
126636view10:51, 8 June 2023Pat hoferBibliography, cleavage arrows, protein-names, phosphorylation of d-secretase by SRPK2
126632view16:04, 7 June 2023Tamara Fitzinger
126624view15:23, 7 June 2023Tamara Fitzinger
126623view15:18, 7 June 2023Pat hoferAdded Bibliography
126622view15:14, 7 June 2023Tamara FitzingerOntology Term : 'frontotemporal dementia' added !
126621view15:14, 7 June 2023Tamara FitzingerOntology Term : 'amyotrophic lateral sclerosis' added !
126620view15:13, 7 June 2023Tamara FitzingerOntology Term : 'Alzheimer's disease' added !
126619view15:13, 7 June 2023Tamara FitzingerOntology Term : 'Parkinson's disease' added !
126618view15:11, 7 June 2023Tamara FitzingerOntology Term : 'neurodegenerative disease' added !
126617view15:08, 7 June 2023Marlenef97Modified description
126616view15:03, 7 June 2023Tamara FitzingerModified title
126615view15:01, 7 June 2023Pat hoferModified title
126614view14:54, 7 June 2023Pat hoferNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
AKT 1ProteinP31749 (Uniprot-TrEMBL) Phosphorylated
AKT 2 ProteinP31751 (Uniprot-TrEMBL) Phosphorylated
AKT 3ProteinQ9Y243 (Uniprot-TrEMBL) Phosphorylated
APPProteinP05067 (Uniprot-TrEMBL)
Alzheimer's diseaseQ11081 (Wikidata)
Amyloid-betaMetaboliteCHEBI:64645 (ChEBI)
BACE1 GeneProductP56817 (Uniprot-TrEMBL)
BDNFProteinP23560 (Uniprot-TrEMBL)
C/EBP10A𝛽ProteinP17676 (Uniprot-TrEMBL) Only a part of the protein (less amino acids)
DOPALMetabolite27978 (ChEBI)
DopamineMetaboliteCHEBI:18243 (ChEBI)
LGMNGeneProductENSG00000100600 (Ensembl)
MAO B ProteinP27338 (Uniprot-TrEMBL)
Microtubule-associated protein tauProteinP10636 (Uniprot-TrEMBL) Phosphorylated
PP2AProteinP62714 (Uniprot-TrEMBL)
ProlegumainProteinQ99538 (Uniprot-TrEMBL)
  • Precursor of δ-secretase
  • Activation by self-cleavage
SET fragmentProtein
SETProteinQ01105 (Uniprot-TrEMBL)
SRPK2 fragmentProtein
SRPK2ProteinP78362 (Uniprot-TrEMBL)
STAT1 ProteinP42224 (Uniprot-TrEMBL)
TDP-43 fragmentProtein
TDP-43ProteinQ13148 (Uniprot-TrEMBL)
Tau (1-368) fragment Protein
TrkBProteinQ16620 (Uniprot-TrEMBL)
α-synuclein (1-103) fragmentProtein
α-synucleinProteinP37840 (Uniprot-TrEMBL)
δ-secretase ProteinQ99538 (Uniprot-TrEMBL)
δ-secretaseProteinQ99538 (Uniprot-TrEMBL) Phosphorylated

Annotated Interactions

No annotated interactions

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