Tau proteins with frontotemporal dementia-17 mutations have both altered expression levels and phosphorylation profiles in differentiated neuroblastoma cells.
The inherited form of frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) has been attributed to mutations in the tau gene. Pathologically, affected FTDP-17 brains share tau aggregates with other tauopathies, the most common being Alzheimer's disease. FTDP-17 mutations may therefore affect tau function leading to tau aggregation and cell loss. Interaction of tau with microtubules is thought to be regulated by phosphorylation. Investigating FTDP-17 mutations transiently expressed as enhanced green fluorescent protein (EGFP)-tagged proteins for the first time in differentiated neuronal cells, we found that two out of three missense mutations showed surprisingly decreased phosphorylation at the pathologically relevant S202/T205 site, mutant EGFP-tau being completely dephosphorylated in most cells. Moreover, phosphorylation at the S396/S404 site was moderately decreased for all mutant isoforms. Although microtubule integrity was not affected, with all mutants tested we demonstrated an increase in cellular tau protein level, some of which is microtubule-bound. Further enhancing this EGFP-tau accumulation by inhibition of tau degradation resulted in the previously less phosphorylated mutant EGFP-tau becoming highly phosphorylated. We conclude that the missense tau mutations primarily result in an excess of neuronal tau, which may interfere with important cellular functions such as axonal transport.
Mack
T G
TG
Department of Neuroscience and Old Age Psychiatry, Institute of Psychiatry, De Crespigny Park, London, UK. till.mack@uni-koeln.de
Dayanandan
R
R
Van Slegtenhorst
M
M
Whone
A
A
Hutton
M
M
Lovestone
S
S
Anderton
B H
BH
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002886:Chromosomes, Human, Pair 17; D003704:Dementia / Q000235:genetics* / Q000378:metabolism*; D015870:Gene Expression / Q000502:physiology; D049452:Green Fluorescent Proteins; D006801:Humans; D007202:Indicators and Reagents / Q000378:metabolism; D007536:Isomerism; D008164:Luminescent Proteins / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000235:genetics; D008870:Microtubules / Q000378:metabolism; D009154:Mutation / Q000502:physiology; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism; D009447:Neuroblastoma; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D014162:Transfection; D014407:Tumor Cells, Cultured; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
D007202:Indicators and Reagents; D008164:Luminescent Proteins; C054369:MAPT protein, human; D008869:Microtubule-Associated Proteins; D016875:tau Proteins; D049452:Green Fluorescent Proteins