Active stress kinase p38 enhances and perpetuates abnormal tau phosphorylation and deposition in Pick's disease.
Abnormal tau hyperphosphorylation and deposition in Pick bodies is a major abnormality in Pick's disease (PiD). This is associated with increased expression of the stress-activated protein kinase, p38 kinase, which has the capacity to phosphorylate tau in vitro. The present study has shown increased expression of phosphorylated p38 (p38-P), which does not cross-react with phospho-tau, in sarcosyl-insoluble fractions enriched in abnormal filaments, and hyperphosphorylated tau in the brain of two PiD cases obtained and processed with very short (less than 2 h) post-mortem delay. Immunohistochemical studies have shown p38-P co-localization in 90% of neurons with Pick bodies, whereas no positive cells are encountered in control brains processed in parallel. Moreover, p38-immunoprecipitated from sarcosyl-insoluble fractions in PiD brains is functionally active as it has the capacity to phosphorylate its specific substrate ATF-2. Combined biochemical, immunohistochemical and functional studies indicate that active p38 kinase is expressed in a very high percentage of Pick bodies, thus suggesting a critical role of this kinase in enhancing and perpetuating tau hyperphosphorylation in PiD.
Puig
Berta
B
Institut de Neuropatologia, Servei d'Anatomia Patològica, Hospital de Bellvitge, carrer Feixa LLarga sn, 08907 Hospitalet de Llobregat, Spain.
Vinals
Francesc
F
Ferrer
Isidre
I
D051698:Activating Transcription Factor 2; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D016022:Case-Control Studies; D002452:Cell Count; D002458:Cell Fractionation / Q000379:methods; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D032446:Myoblasts; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D020774:Pick Disease of the Brain / Q000201:enzymology / Q000378:metabolism*; D011233:Precipitin Tests / Q000379:methods; D013194:Staining and Labeling; D014157:Transcription Factors / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases; D016875:tau Proteins / Q000378:metabolism*
C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; C497106:Atf2 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D014157:Transcription Factors; D016875:tau Proteins; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases