Progressive neurodegeneration in C. elegans model of tauopathy
Introduction
Microtubule-binding protein tau, which promotes tubulin polymerization and stabilizes microtubules, was identified as the major component of the framework of neurofibrillary tangles (NFT) found in the brain affected by so called tauopathy, the conditions such as Alzheimer's disease (AD) and frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) (Buee et al., 2000, Lee et al., 2001). Patients affected by FTDP-17, a hereditary familial tauopathy, develop execution problems, behavioral abnormalities, often parkinsonism, and finally dementia. Identification of >20 exonic and intronic mutations in the tau gene in FTDP-17 families indicates that tau is directly involved in neurodegeneration and neuronal loss (Clark et al., 1998, Hutton et al., 1998, Poorkaj et al., 1998, Reed et al., 2001, Spillantini et al., 1998).
To date, various models for tauopathy using mouse, fly, nematode, and zebra fish have been produced. By introducing wild-type (WT) or FTDP-17 mutant tau gene into mice, characteristic pathological changes and some clinical features of FTDP-17 were recaptured (Gotz et al., 2001, Ishihara et al., 1999, Ishihara et al., 2001, Lewis et al., 2000, Lim et al., 2001, Probst et al., 2000, Spittaels et al., 1999, Tanemura et al., 2001, Tanemura et al., 2002, Tatebayashi et al., 2002). In a fly model, severe neurodegeneration was found but without any inclusions (Mudher et al., 2004, Nishimura et al., 2004, Wittmann et al., 2001). A nematode model also showed both behavioral change and neurodegeneration (Kraemer et al., 2003). These models provide both invaluable information about the nature of neurodegeneration caused by tauopathy and an important tool for screening for effective therapeutic compounds. However, despite the availability of model animals, detailed pictures of neurodegeneration have remained unknown largely because of the complexity of the nervous system. We thus generated transgenic nematode expressing human WT tau or two kinds of FTDP-17 mutant tau (P301L and R406W; numbered according to the 441-residue R406W; numbered according to the 441-residue isoform) in six mechanosensory neurons, ALML/R, AVM, PLML/R, and PVM, also called touch neurons (Chalfie and Thomson, 1982). They can be readily traced to their fine neuronal processes under microscopy, a condition which is difficult to obtain in other models.
These neurons are characterized by distinct microtubules of a larger diameter that consist of 15 protofilaments (instead of 11) and by expression of MEC-12 and MEC-7 and distinct types of α- and β-tubulin (Fukushige et al., 1999, Hamelin et al., 1992, Savage et al., 1989). Because the mutations of either distinct tubulin or target disruption of the touch neurons eliminate the sensitivity to gentle touch (Chalfie and Au, 1989, Chalfie and Sulston, 1981), these six neurons should govern the touch response. Thus, a decrease in the touch sensitivity reflects loss-of-function of the touch neurons (Riddle et al., 1997).
Section snippets
Growth and maintenance of nematode strains
Caenorhabditis elegans strains were maintained under the standard conditions, according to the methods of Brenner (1974) with modification by Way and Chalfie (1988). Wild-type C. elegans indicates the Bristol strain N2. Genetic methods were employed as per those described by Brenner (1974). In addition to the wild-type worm, the wild-type ones integrated with the human genes, tau, GSK3β, and HSP70, were used. Strains with the following mutations were used for genetic cross: ced-3 IV (n717),
Progressive decrease in the touch response of tau-transgenic worms
To establish the tau-transgenic (Tg) worm lines, five WT4R-Tg lines (tmIs82, tmIs83, tmIs84, tmIs85, and tmIs171), two WT3R-Tg lines (tmIs110 and tmIs173), three P301L-Tg lines (tmIs81, tmIs178, and tmIs179), and four R406W-Tg lines (tmIs146, tmIs147, tmIs148, and tmIs149) were generated by stable chromosomal integration together with a dominant roller marker, as described in Materials and methods. An integrated line (tmIs128) expressing the roller marker only was also generated and used as the
Discussion
The present C. elegans model of tauopathy complements other animal models and may add distinct aspects on the tau-mediated neuronal toxicity. Six neurons of C. elegans govern the gentle touch response: ALML, ALMR, and AVM, and especially the former two, control the touch sense of the anterior half of the body; PLML, PLMR, and PVM, and especially the former two, control that of the posterior half of the body. When all of the touch neurons are eliminated, the touch response is completely lost
Acknowledgments
We thank the Caenorhabditis Genetics Center, which is funded by the NIH National Center for Research Resources, for some nematode strains used in this study, Dr. H. Mori (Osaka City Univ.) for providing pool-2 antibody, Dr. G. Sobue (Nagoya Univ.) for providing hsp70 cDNAs, and Dr. A. Takashima (RIKEN BSI) for providing tau-c antibody and gsk-3β cDNAs. This work was supported in part by a grant-in-aid for Scientific Research on Priority Areas–Advanced Brain Science Project–from the Ministry of
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These authors equally contributed to this work.