title: Age-dependent axonal transport and locomotor changes and tau hypophosphorylation in a "P301L" tau knockin mouse.
abstract: Tauopathies are characterized by hyperphosphorylation of the microtubule-associated protein tau and its accumulation into fibrillar aggregates. Toxic effects of aggregated tau and/or dysfunction of soluble tau could both contribute to neural defects in these neurodegenerative diseases. We have generated a novel knockin mouse model of an inherited tauopathy, frontotemporal dementia with parkinsonism linked to tau mutations on chromosome 17 (FTDP-17T). We incorporated a single mutation, homologous to the common FTDP-17T P301L mutation, directly into the endogenous mouse gene, mimicking the human disease situation. These mice express P301L-equivalent mutant tau at normal physiological levels from the knockin allele. Importantly, in contrast to existing transgenic mouse models that overexpress human P301L mutant tau, no overt tau pathology developed during the normal lifespan of the knockin mice. In fact, overall phosphorylation of tau was reduced, perhaps due to reduced microtubule binding. However, homozygous knockin mice did display intriguing age-dependent changes in axonal transport of mitochondria, and increased spontaneous locomotor activity in old age. These could represent early consequences of the tau dysfunction that eventually precipitates pathogenesis in humans.
authors.affiliation: The Babraham Institute, Babraham, Cambridge, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Gilley
authors.forename: Anjan
authors.initials: A
authors.lastname: Seereeram
authors.forename: Kunie
authors.initials: K
authors.lastname: Ando
authors.forename: Suzanne
authors.initials: S
authors.lastname: Mosely
authors.forename: Simon
authors.initials: S
authors.lastname: Andrews
authors.forename: Martin
authors.initials: M
authors.lastname: Kerschensteiner
authors.forename: Thomas
authors.initials: T
authors.lastname: Misgeld
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Brion
authors.forename: Brian
authors.initials: B
authors.lastname: Anderton
authors.forename: Diane P
authors.initials: DP
authors.lastname: Hanger
authors.forename: Michael P
authors.initials: MP
authors.lastname: Coleman
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001370:Axonal Transport / Q000235:genetics; D001369:Axons / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D055879:Gene Knock-In Techniques; D006801:Humans; D006948:Hyperkinesis / Q000235:genetics / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation / Q000235:genetics; D061251:Primary Cell Culture; D024801:Tauopathies / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D016875:tau Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*
chemical_list: D016875:tau Proteins