Progressive neurodegeneration in C. elegans model of tauopathy.
Discovery of various mutations in the tau gene among frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) families suggests gain-of-toxic function of wild-type or mutant tau as the mechanism for extensive neuronal loss. We thus generated transgenic nematode (Caenorhabditis elegans) expressing wild-type or mutant (P301L and R406W) tau in the touch (mechanosensory) neurons. Whereas the worm expressing wild-type tau showed a small decrease in the touch response across the lifespan, the worm expressing mutant tau displayed a large and progressive decrease. When the touch neurons lost their function, neuritic abnormalities were found prominent, and microtubular loss became remarkable in the later stage. A substantial fraction of degenerating neurons developed tau accumulation in the cell body and neuronal processes. This neuronal dysfunction is not related to the apoptotic process because little recovery from touch abnormality was observed in the ced-3 or ced-4-deficient background. Expression of GSK3 brought about slight deterioration in the touch response, while expression of HSP70 led to some improvement.
Miyasaka
Tomohiro
T
Department of Neuropathology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Tokyo 113-0033, Japan.
Ding
Zhen
Z
Gengyo-Ando
Keiko
K
Oue
Miho
M
Yamaguchi
Haruyasu
H
Mitani
Shohei
S
Ihara
Yasuo
Y
D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D008465:Mechanoreceptors / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D046529:Microscopy, Electron, Transmission; D008870:Microtubules / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009420:Nervous System / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D016501:Neurites / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D009474:Neurons / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D018384:Oxidative Stress / Q000235:genetics; D020886:Somatosensory Disorders / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D024801:Tauopathies / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D014110:Touch / Q000235:genetics; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
D018840:HSP70 Heat-Shock Proteins; D016875:tau Proteins; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3