Changed conformation of mutant Tau-P301L underlies the moribund tauopathy, absent in progressive, nonlethal axonopathy of Tau-4R/2N transgenic mice.
Protein tau-3R/4R isoform ratio and phosphorylation regulates binding to microtubules and, when disturbed by aging or mutations, results in diverse tauopathies and in neurodegeneration. The underlying mechanisms were studied here in three transgenic mouse strains with identical genetic background, all expressing the tau-4R/2N isoform driven specifically in neurons by the thy1 gene promoter. Two strains, expressing human tau-4R/2N or mutant tau-4R/2N-P301L at similar, moderate levels, developed very different phenotypes. Tau-4R/2N mice became motor-impaired already around age 6-8 weeks, accompanied by axonopathy (dilatations, spheroids), but no tau aggregates, and surviving normally. In contrast, tau-P301L mice developed neurofibrillary tangles from age 6 months, without axonal dilatations and, despite only minor motor problems, all succumbing before the age of 13 months. The third strain, obtained by tau knock-out/knock-in (tau-KOKI), expressed normal levels of wild-type human tau-4R/2N replacing all mouse tau isoforms. Tau-KOKI mice survived normally with minor motor problems late in life and without any obvious pathology. Biochemically, a fraction of neuronal tau in aging tau-P301L mice was hyperphosphorylated concomitant with conformational changes and aggregation, but overall, tau-4R/2N was actually more phosphorylated than tau-P301L. Significantly, tau with changed conformation and with hyperphosphorylation colocalized in the same neurons in aging tau-P301L mice. Taken together, we conclude that excessive binding of tau-4R/2N as opposed to reduced binding of tau-P301L to microtubules is responsible for the development of axonopathy and tauopathy, respectively, in tau-4R/2N and tau-P301L mice and that the conformational change of tau-P301L is a major determinant in triggering the tauopathy.
Terwel
Dick
D
Experimental Genetics Group, Department of Human Genetics, KU Leuven, B-3000 Leuven, Belgium.
Lasrado
Reena
R
Snauwaert
Johan
J
Vandeweert
Erno
E
Van Haesendonck
Chris
C
Borghgraef
Peter
P
Van Leuven
Fred
F
D000375:Aging; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology; D002490:Central Nervous System / Q000473:pathology / Q000503:physiopathology; D000939:Epitopes / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009043:Motor Activity; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011487:Protein Conformation; D024801:Tauopathies / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D016875:tau Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism
D000939:Epitopes; D016875:tau Proteins