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
- Kraemer BC, Zhang B, Leverenz JB, Thomas JH, Trojanowski JQ, Schellenberg GD. 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.