Stable expression in Chinese hamster ovary cells of mutated tau genes causing frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17).
Extensive neuronal loss and aggregation of tau as cytoplasmic inclusions in neurons and glial cells in selected cortical and subcortical regions is the most striking characteristic of frontotemporal dementia and parkinsonism linked to chromosome 17, which is caused by exonic or intronic mutations in the tau gene. Here, we examined the effects of four exonic mutations in four-repeat tau using stably transfected Chinese hamster ovary cells. The proportion of polymerized tubulin was the largest in the P301L transfectant. G272V and P301L transfectants showed greater instability of microtubules in the presence of Colcemid than wild-type tau, V337M, or R406W transfectants. Thus no distinct phenotypes were shared by the mutant tau transfectants with regard to microtubule assembly and stability. Unexpectedly, R406W showed low and negligible levels of phosphorylation at Thr 231 and Ser 396, respectively, in the transfectant. This presents a sharp contrast to the observation that tau aggregates in R406W-affected brains are heavily phosphorylated at these two sites. This result suggests that hyperphosphorylation at these sites cannot occur in the tau R406W bound to microtubules, and thus that the hyperphosphorylated species of tau may be generated only after disruption of microtubules.
Matsumura
N
N
Department of Neuropathology, Faculty of Medicine, University of Tokyo, Japan.
Yamazaki
T
T
Ihara
Y
Y
D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D006224:Cricetinae; D003571:Cytochalasin B / Q000494:pharmacology; D003703:Demecolcine / Q000494:pharmacology; D003704:Dementia / Q000235:genetics*; D015870:Gene Expression; D008040:Genetic Linkage; D006801:Humans; D007150:Immunohistochemistry; D008870:Microtubules / Q000187:drug effects / Q000502:physiology; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics*; D013347:Subcellular Fractions / Q000378:metabolism; D014162:Transfection; D016875:tau Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism
D016875:tau Proteins; D003571:Cytochalasin B; D003703:Demecolcine