A role for FKBP52 in Tau protein function.
Tau is a microtubule-associated protein, which is widely expressed in the central nervous system, predominantly in neurons, where it regulates microtubule dynamics, axonal transport, and neurite outgrowth. The aberrant assembly of Tau is the hallmark of several human neurodegenerative diseases, collectively known as tauopathies. They include Alzheimer's disease, Pick's disease, progressive supranuclear palsy, and frontotemporal dementia and parkinsonism linked to chromosome 17. Several abnormalities in Tau, such as hyperphosphorylation and aggregation, alter its function and are central to the pathogenic process. Here, we describe biochemical and functional interactions between FKBP52 and Tau. FKBP52 is a member of the FKBP (FK506-binding protein) family that comprises intracellular protein effectors of immunosuppressive drugs (such as FK506 and rapamycin). We found that FKBP52, which is abundant in brain, binds directly and specifically to Tau, especially in its hyperphosphorylated form. The relevance of this observation was confirmed by the colocalization of both proteins in the distal part of the axons of cortical neurons and by the antagonistic effect of FKBP52 on the ability of Tau to promote microtubule assembly. Overexpression of FKBP52 in differentiated PC12 cells prevented the accumulation of Tau and resulted in reduced neurite length. Taken together, these findings indicate a role for FKBP52 in Tau function and may help to decipher and modulate the events involved in Tau-induced neurodegeneration.
Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 788, Université Paris XI, Kremlin Bicêtre 94276, France.
Béatrice
B
Chambraud
Elodie
E
Sardin
Julien
J
Giustiniani
Omar
O
Dounane
Michael
M
Schumacher
Michel
M
Goedert
Etienne-Emile
EE
Baulieu
D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D004318:Doxycycline / Q000494:pharmacology; D006801:Humans; D008297:Male; D008870:Microtubules / Q000378:metabolism; D020932:Nerve Growth Factor / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects / Q000502:physiology*; D016716:PC12 Cells; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D014162:Transfection; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D016875:tau Proteins; D020932:Nerve Growth Factor; D022021:Tacrolimus Binding Proteins; C403485:tacrolimus binding protein 4; D004318:Doxycycline