Human tau-whether normal or a disease-causing mutant-does not make for a healthy C. elegans. In the Early Edition of PNAS, Gerry Schellenberg and colleagues report that both types of transgenic tau lead to behavioral, synaptic, and pathologic abnormalities in the worms, though the mutant tau has earlier and more severe consequences. The temporal appearance of the various abnormalities suggests that aggregation is not necessary for tau to induce neuronal dysfunction in this model.

Schellenberg and first author Brian Kraemer, along with their colleagues at the University of Washington in Seattle and the University of Pennsylvania in Philadelphia, introduced into C. elegans the gene for the most common normal human tau variant (4R1N), and also for several mutations that cause frontotemporal dementia with parkinsonism-chromosome 17 (FTDP-17). This tauopathy is caused by mutations in MAPT, the gene encoding tau, though the mechanisms by which mutant tau leads to neurodegeneration are not known.

All the transgenes led to reduced lifespan, uncoordinated locomotion, and other phenotypes typical of C. elegans neuronal defect mutants. It is noteworthy that normal, as well as mutant, tau had this injurious effect. However, the mutant tau (especially V337M) was more severe, a trend that held for most of the pathological findings, as well. Among these were the accumulation of insoluble tau, neurodegeneration, and loss of neurons. The only pathological feature not shared by normal and mutant transgenics was tau-positive aggregates in degenerating axons-only the mutant tau worms had these.

Both normal and mutant tau led to presynaptic, but not postsynaptic, defects in cholinergic neurotransmission. Finally, the researchers found that tau was phosphorylated at some of the same sites as hyperphosphorylated tau in AD and FTDP-17, but they were not able to show any correlation between phosphorylation and severity of phenotype.

An important difference between this model and mouse transgenic models of tauopathy is that the behavioral impairments were noted before tau began to form aggregates, suggesting that while aggregation may contribute to eventual neuronal loss, it is not necessary to cause neuronal dysfunction. The authors suggest that perhaps the behavioral test used in rodents (hind limb function) may not be sensitive enough to detect early phenotypic changes due to nonaggregated tau. See also related ARF Live Discussion.—Hakon Heimer


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  1. This is an excellent study on a novel C. elegans model for FTDP-17 tauopathies, with an eventual bearing on AD. The worms were humanized for tau and overexpress either wild-type or mutant tau in isoform ¡§4R1N,¡¨ i.e., containing the four microtubule binding domains and one N-terminal insert, the most abundant isoform in human brain. The C. elegans model excels in its simplicity and clarity of pathology, with the evident (for worms) rapidity of evolution (~9 days) and the very distinct behavioral and neuropathological defects.

    It is amazing to see the cellular pathological defects, recapitulating what is observed in brain and spinal cord of transgenic mice overexpressing human tau-4R in neurons, reported by us (Spittaels et al, 1999; 2000) and others, and comprehensively discussed and referenced in this paper. The study further highlights that the differences in phenotype caused by either wild-type tau or FTD-mutant tau are minor, and this emphazises the problem and our lack of understanding of the actual molecular contribution of expressed and silent FTD-mutants to the actual clinical phenotype. Of some concern for correct molecular interpretation is the difference—or the lack of it—between wild-type and FTD mutant tau for parameters like survival (similar) and neuronal loss (same for all) as opposed to axonal tau-aggregates seen only for tau-V337M.

    Equally amazing is how this model so clearly pinpoints the problems and questions that the ¡§mammalian¡¨ model builders have faced for years. First, what is the role of tau-phosphorylation (normal or ¡§hyper¡¨) in causing the defects and in forming the tau aggregates? We expect and await evidence for an important role for GSK3b in this model, as in transgenic mice (Spittaels et al, 2000). Second, what is (or are) the actual molecular culprit(s), i.e., single molecules of misphosphorylated tau or small aggregates? Third, what is the exact time course of events, i.e., phosphorylation before or after (smaller) aggregates are formed? Fourth, what is the underlying mechanism of disturbed presynaptic transmission, i.e., simply disturbed axonal transport (Terwel et al, 2003)? How does this operate in C. elegans in terms of microtubular structure and stabilization by microtubule-associated proteins (MAPs), if any, and how are they counteracted by human tau?

    Without exception, these are important questions that can and will be addressed and answered by further work in this model, which, thanks to its speed and ¡§transparency,¡¨ hopefully will improve mammalian modeling.

    Finally, one cannot but be reminded of the amyloid side of neurodegeneration, where attention has finally shifted to the smaller cell-associated aggregated peptides, and away from large aggregates, i.e., the amyloid plaques that have been advocated too long as the major and even the initial problem. As clearly stated in this work, we have appreciated for some time now that for amyloid and tau, and indeed for any protein, ¡§¡K low-level aggregates are ¡K sufficient to disrupt neuronal function.¡¨ On the other hand, a chemical property, e.g., hydrophobic propensity to form b-sheets, that causes a neuronal defect by interfering with a given process is likely to lead also to self-aggregation. But all are separate phenotypic traits, i.e., different externalizations or embodiments of that single chemical property.

    This should not be taken to imply that aggregates of amyloid or tau, or any protein, for that matter, are ¡§harmless.¡¨ They might be initially, and could be even beneficial by lowering the active concentration of the monomer. In the long run, excessive accumulation, be it intra- or extracellular, will trigger (auto)-destructive mechanisms that will kill neurons and eventually, the organism. This is the ¡§late phase¡¨ of disease as observed clinically in patients, as well as in transgenic mice and other models, and so elegantly demonstrated in the C. elegans model here. Evidently, without minimizing the importance of proper treatment of the ¡§late phase,¡¨ one hopes to obtain from models—any model—insight into the very early phases of neurodegeneration, to prevent, stall, curb, or even reverse dementia.

    Spittaels K, Van den Haute C, Van Dorpe J, Bruynseels K, Vandezande K, Laenen I, Geerts H, Mercken M, Sciot R, Van Lommel A, Loos R, Van Leuven F. Prominent axonopathy in the brain and spinal cord of transgenic mice overexpressing four-repeat human tau protein. Am J Pathol. 1999 Dec;155(6):2153-65. Abstract

    Spittaels K, Van den Haute C, Van Dorpe J, Geerts H, Mercken M, Bruynseels K, Lasrado R, Vandezande K, Laenen I, Boon T, Van Lint J, Vandenheede J, Moechars D, Loos R, Van Leuven F. Glycogen synthase kinase-3ƒÒ phosphorylates protein tau and rescues the axonopathy in the CNS of human four-repeat tau transgenic mice. J Biol Chem. 2000 Dec 29;275(52):41340-9. Abstract

    Terwel D, Dewachter L, Van Leuven F. Axonal transport, protein tau and neurodegeneration in Alzheimer¡¦s disease. Neuromolecular Med. 2002;2(2):151-65. Review. Abstract


    . Prominent axonopathy in the brain and spinal cord of transgenic mice overexpressing four-repeat human tau protein. Am J Pathol. 1999 Dec;155(6):2153-65. PubMed.

    . Glycogen synthase kinase-3beta phosphorylates protein tau and rescues the axonopathy in the central nervous system of human four-repeat tau transgenic mice. J Biol Chem. 2000 Dec 29;275(52):41340-9. PubMed.

    . Axonal transport, tau protein, and neurodegeneration in Alzheimer's disease. Neuromolecular Med. 2002;2(2):151-65. PubMed.

  2. Kraemer and colleagues have established a new animal model for the study of tau pathology: transgenic C. elegans nematode worms expressing normal and mutant human tau. These researchers find that transgenic worms with neuronal expression of human tau have a dramatic "Uncoordinated" phenotype indicative of neuronal dysfunction. Although expression of either normal or Frontotemporal Dementia with Parkinsonism-chromosome 17 (FTDP-17)-mutant tau induces behavioral abnormalities, the mutant tau forms appear to be more toxic, and to more readily form insoluble tau with age. The more aggressive pathology associated with the FTDP-17 mutant tau is consistent with observations in human patients and transgenic mouse models, supporting the notion that a similar underlying pathologic mechanism may be at work in the transgenic worms. Given that Alzheimer's disease involves the deposition of non-mutant tau, the observation that wild-type tau is also toxic in this model (as is also observed in transgenic fly models) suggests that this model might also have relevance to AD.

    Although there are clear similarities between the worm model and human tauopathies, some possible differences were observed. Most prominently, tau transgenic worms show clear neuronal dysfunction preceding detectable formation of insoluble tau. This could indicate that toxicity is due to an intermediate form of tau that precedes the formation of fully aggregated tau (as has been suggested for b amyloid peptide toxicity). Alternatively, tau toxicity and tau aggregation may really be separable processes in this model. In addition, no obvious relationship was observed between tau hyperphosphorylation and tau aggregation.

    The primary advantage of this new worm model is the opportunity to do forward genetic screens, i.e., identification of mutations that suppress the toxic effects of tau. In theory, this approach can identify the molecular targets of tau toxicity, a key and still-unresolved issue in the field. In addition, the small size and readily assayed phenotype of the tau transgenic animals might allow high-throughput testing for drugs that block tau toxicity.


Other Citations

  1. ARF Live Discussion

Further Reading

Primary Papers

  1. . Neurodegeneration and defective neurotransmission in a Caenorhabditis elegans model of tauopathy. Proc Natl Acad Sci U S A. 2003 Aug 19;100(17):9980-5. PubMed.