Phosphorylation of protein Tau by GSK3β prolongs survival of bigenic Tau.P301L×GSK3β mice by delaying brainstem tauopathy.
Tau.P301L transgenic mice suffer precocious mortality between ages 8 and 11 months, resulting from upper airway defects caused by tauopathy in autonomic brainstem circuits that control breathing (Dutschmann et al., 2010). In individual mice, the clinical phenotype evolves progressively and rapidly (3-6weeks) from clasping, over general motor impairment to severe reduction in body-weight into the terminal phase that announces imminent death (<3days). Surprisingly, co-expression of GSK3β with Tau.P301L significantly prolonged survival of bigenic biGT mice (Terwel et al., 2008), which we here assign to delayed development of brainstem tauopathy. Eventually, brainstem tauopathy became as prominent in old biGT mice in the specified brainstem nuclei as in the parental Tau.P301L mice, resulting in similar clinical deterioration and terminal phase preceding death, although at later age. Biochemically, in both genotypes the pathway to neurofibrillary tangles and neuropil threads was similar: phosphorylation of protein Tau and formation of soluble oligomers and insoluble aggregates, ending in the typical tangles and threads of tauopathy. The extra GSK3β activity led to expected increased phosphorylation of protein Tau, particularly at residues S262 and S396, which we must conclude to delay the aggregation of protein Tau in the brainstem of aging biGT mice. The unexpected, paradoxical alleviation of the brainstem problems in biGT mice allowed them to grow older and thereby develop more severe tauopathy in forebrain than Tau.P301L mice, which succumb at younger age.
Experimental Genetics Group - LEGTEGG, Dept. Human Genetics, KU Leuven, B-3000 Leuven, Belgium.
Natalia
N
Crespo-Biel
Experimental Genetics Group - LEGTEGG, Dept. Human Genetics, KU Leuven, B-3000 Leuven, Belgium.
Clara
C
Theunis
Experimental Genetics Group - LEGTEGG, Dept. Human Genetics, KU Leuven, B-3000 Leuven, Belgium.
Peter
P
Borghgraef
Experimental Genetics Group - LEGTEGG, Dept. Human Genetics, KU Leuven, B-3000 Leuven, Belgium.
Benoit
B
Lechat
Experimental Genetics Group - LEGTEGG, Dept. Human Genetics, KU Leuven, B-3000 Leuven, Belgium.
Herman
H
Devijver
Experimental Genetics Group - LEGTEGG, Dept. Human Genetics, KU Leuven, B-3000 Leuven, Belgium.
Hervé
H
Maurin
Experimental Genetics Group - LEGTEGG, Dept. Human Genetics, KU Leuven, B-3000 Leuven, Belgium. Electronic address: fred.vanleuven@med.kuleuven.be.
Fred
F
Van Leuven
D000818:Animals; D001921:Brain / Q000201:enzymology / Q000378:metabolism; D001933:Brain Stem / Q000201:enzymology* / Q000378:metabolism; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D016019:Survival Analysis; D024801:Tauopathies / Q000201:enzymology* / Q000378:metabolism; D016875:tau Proteins / Q000737:chemistry* / Q000378:metabolism*
D016875:tau Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
Brainstem; GSK3; Protein Tau; Survival; Tauopathy