Wnt-pathway activation during the early stage of neurodegeneration in FTDP-17 mice.
Glycogen synthase kinase-3beta (GSK-3beta), a key component of the Wnt signaling pathway, has been recognized as an important tau kinase with a potential pathogenic role in dementia. We have previously shown that GSK-3beta-induced tau-hyperphosphorylation and Wnt-activation enhance tau-induced degeneration in Drosophila. Here, we demonstrate that Wnt-activation occurs prior to 3 months of age in the JNPL3 mouse model of frontotemporal dementia (FTD). We observed that GSK-3beta becomes associated with insoluble tau, concomitant with the increase in the downstream Wnt-pathway component beta-catenin. We demonstrate that this induces downstream Wnt signaling via the activation of nuclear transcription factors associated with beta-catenin, suggesting that Wnt-pathway activation is an early feature of the neurodegenerative process.
Wiedau-Pazos
Martina
M
Department of Neurology, David Geffen School of Medicine at UCLA, 635 Charles E. Young Drive South, Los Angeles, CA 90095, USA. mwiedau@mednet.ucla.edu
Wong
Eugene
E
Solomon
Esther
E
Alarcon
Maricela
M
Geschwind
Daniel H
DH
D000375:Aging / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D003704:Dementia / Q000378:metabolism*; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015398:Signal Transduction; D013116:Spinal Cord / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*
D051153:Wnt Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3