Coexpression of GSK-3beta corrects phenotypic aberrations of dorsal root ganglion cells, cultured from adult transgenic mice overexpressing human protein tau.
Coexpression of constitutively active GSK-3beta[S9A] rescued the axonal pathology induced by overexpression of human tau in transgenic mice (Spittaels et al., (2000) J. Biol. Chem. 275, 41340-41349). We isolated dorsal root ganglion (DRG) neuronal cultures from adult tau4R- and tau4R x GSK-3beta-transgenic mice to define the mechanisms at the cellular and subcellular level. DRG from tau4R-transgenics showed a reduced sprouting capacity while density and stability of microtubules in the axonal processes were significantly increased. Video-enhanced contrast microscopy demonstrated a dramatic inhibition of fast axonal transport. Coexpression of GSK-3beta increased tau phosphorylation and reversed the effects on microtubule stability and saltatory motion. In DRG from GSK-3beta single transgenics, increased tau phosphorylation was evident without any major effects on microtubule stability or axonal transport. These observations support the hypothesis that excess tau competed with motor-proteins for binding to microtubules and/or that a rigid microtubular system inhibits axonal transport.
Nuydens
R
R
CNS Discovery Research, Janssen Research Foundation, Beerse, Belgium.
Van Den Kieboom
G
G
Nolten
C
C
Verhulst
C
C
Van Osta
P
P
Spittaels
K
K
Van den Haute
C
C
De Feyter
E
E
Geerts
H
H
Van Leuven
F
F
D000107:Acetylation; D000367:Age Factors; D000818:Animals; D001370:Axonal Transport / Q000502:physiology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics* / Q000378:metabolism*; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000201:enzymology* / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic; D038362:Glycogen Synthase Kinase 3; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008870:Microtubules / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D010641:Phenotype; D010766:Phosphorylation; D014404:Tubulin / Q000032:analysis / Q000378:metabolism; D016875:tau Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*
D014404:Tubulin; D016875:tau Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3