Proteasome-caspase-cathepsin sequence leading to tau pathology induced by prostaglandin J2 in neuronal cells.

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  • Author(s): Arnaud LT;Arnaud LT; Myeku N; Figueiredo-Pereira ME
  • Source:
    Journal of neurochemistry [J Neurochem] 2009 Jul; Vol. 110 (1), pp. 328-42. Date of Electronic Publication: 2009 May 03.
  • Publication Type:
    Journal Article; Research Support, N.I.H., Extramural
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Wiley on behalf of the International Society for Neurochemistry Country of Publication: England NLM ID: 2985190R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1471-4159 (Electronic) Linking ISSN: 00223042 NLM ISO Abbreviation: J Neurochem Subsets: MEDLINE
    • Publication Information:
      Publication: 2001- : Oxford, UK : Wiley on behalf of the International Society for Neurochemistry
      Original Publication: New York : Raven Press
    • Subject Terms:
      Caspases/*metabolism ; Cathepsins/*metabolism ; Neurofibrillary Tangles/*metabolism ; Prostaglandin D2/*analogs & derivatives ; Proteasome Endopeptidase Complex/*metabolism ; tau Proteins/*metabolism; Alzheimer Disease/metabolism ; Alzheimer Disease/physiopathology ; Animals ; Apoptosis/drug effects ; Apoptosis/physiology ; Caspases/drug effects ; Cathepsins/drug effects ; Cell Line, Tumor ; Cells, Cultured ; Encephalitis/metabolism ; Encephalitis/physiopathology ; Enzyme Activation/drug effects ; Enzyme Activation/physiology ; Humans ; Lysosomes/drug effects ; Lysosomes/metabolism ; Neurofibrillary Tangles/drug effects ; Prostaglandin D2/metabolism ; Prostaglandin D2/toxicity ; Proteasome Endopeptidase Complex/drug effects ; Rats ; Signal Transduction/drug effects ; Signal Transduction/physiology ; Tauopathies/metabolism ; Tauopathies/physiopathology ; Ubiquitination/drug effects ; Ubiquitination/physiology ; tau Proteins/drug effects
    • Abstract:
      Neurofibrillary tangles (NFT) are a hallmark of Alzheimer's disease. The major neurofibrillary tangle component is tau that is truncated at Asp421 (Deltatau), hyperphosphorylated and aggregates into insoluble paired helical filaments. Alzheimer's disease brains also exhibit signs of inflammation manifested by activated astrocytes and microglia, which produce cytotoxic agents among them prostaglandins. We show that prostaglandin (PG) J2, an endogenous product of inflammation, induces caspase-mediated cleavage of tau, generating Deltatau, an aggregation prone form known to seed tau aggregation prior to neurofibrillary tangle formation. The initial event observed upon PGJ2-treatment of human neuroblastoma SK-N-SH cells was the build-up of ubiquitinated (Ub) proteins indicating an early disruption of the ubiquitin-proteasome pathway. Apoptosis kicked in later, manifested by caspase activation and caspase-mediated cleavage of tau at Asp421 and poly (ADP-ribose) polymerase. Furthermore, cathepsin inhibition stabilized Deltatau suggesting its lysosomal clearance. Upon PGJ2-treatment tau accumulated in a large perinuclear aggregate. In rat E18 cortical neuronal cultures PGJ2-treatment also generated Deltatau detected in dystrophic neurites. Levels of Deltatau were diminished by caspase 3 knockdown using siRNA. PGD2, the precursor of PGJ2, produced some Deltatau. PGE2 generated none. Our data suggest a potential sequence of events triggered by the neurotoxic product of inflammation PGJ2 leading to tau pathology. The accumulation of Ub proteins is an early response. If cells fail to overcome the toxic effects induced by PGJ2, including accumulation of Ub proteins, apoptosis kicks in triggering caspase activation and tau cleavage, the clearance of which by cathepsins could be compromised culminating in tau pathology. Our studies are the first to provide a mechanistic link between inflammation and tau pathology.
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    • Grant Information:
      U54 NS041073-06A10001 United States NS NINDS NIH HHS; U54 NS041073-080001 United States NS NINDS NIH HHS; RR03037 United States RR NCRR NIH HHS; G12 RR003037-245472 United States RR NCRR NIH HHS; NS41073 United States NS NINDS NIH HHS; U54 NS041073-100001 United States NS NINDS NIH HHS; U54 NS041073-090001 United States NS NINDS NIH HHS; U54 NS041073-070001 United States NS NINDS NIH HHS; G12 RR003037 United States RR NCRR NIH HHS; U54 NS041073 United States NS NINDS NIH HHS
    • Accession Number:
      0 (tau Proteins)
      60203-57-8 (9-deoxy-delta-9-prostaglandin D2)
      EC 3.4.- (Cathepsins)
      EC 3.4.22.- (Caspases)
      EC 3.4.25.1 (Proteasome Endopeptidase Complex)
      RXY07S6CZ2 (Prostaglandin D2)
    • Publication Date:
      Date Created: 20090522 Date Completed: 20090821 Latest Revision: 20211020
    • Publication Date:
      20231215
    • Accession Number:
      PMC2889249
    • Accession Number:
      10.1111/j.1471-4159.2009.06142.x
    • Accession Number:
      19457109