Neurodegenerative tauopathy in the worm.

T he most common neurodegenerative diseases are characterized by the presence of abnormal filamentous protein inclusions in nerve cells of the brain. In Alzheimer’s disease, these inclusions are made of hyperphosphorylated tau protein (1). Together with the extracellular -amyloid deposits, they constitute the defining neuropathological characteristics of Alzheimer’s disease. Tau inclusions, in the absence of extracellular deposits, are characteristic of progressive supranuclear palsy, corticobasal degeneration, Pick’s disease, argyrophilic grain disease, and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) (1). The identification of mutations in Tau in FTDP-17 (2–4) has established that dysfunction of tau protein is central to the neurodegenerative process. At an experimental level, the expression of mutant human tau in nerve cells is leading to improved models of neurodegeneration. In this issue of PNAS, Kraemer et al. (5) describe lines of Caenorhabditis elegans expressing transgenic wild-type and mutant human tau protein. They represent an important addition to existing transgenic models for the human tauopathies. Tau protein is widely expressed in the mammalian nervous system, where it plays a role in the assembly and stabilization of microtubules (1). In adult human brain, there are six isoforms of tau, produced from a single gene by alternative mRNA splicing (6, 7). They differ by the presence or absence of a 29or 58-aa insert in the N-terminal half and by the inclusion, or not, of a 31-aa repeat, encoded by exon 10 of Tau, in the C-terminal half of the protein (Fig. 1a). The exclusion of exon 10 leads to the production of three isoforms, each containing three repeats, and its inclusion leads to a further three isoforms, each containing four repeats. The repeats constitute the microtubule-binding region of tau, and similar levels of threeand four-repeat isoforms are expressed in adult human brain. Repeat sequences homologous to those in tau are also present in the high-molecular-weight microtubuleassociated proteins MAP2 and MAP4. The genomes of C. elegans and Drosophila melanogaster encode only one protein with tau-like repeats. Tau mutations in FTDP-17 are either missense, deletion, or silent mutations in the coding region, or intronic mutations located close to the splice-donor site of the intron following exon 10 (1). So far, 31 different mutations have been described in 80 families with FTDP-17 (Fig. 1). Functionally, Tau mutations fall into two largely nonoverlapping categories, those that influence the alternative splicing of tau pre-mRNA and those whose primary effect is at the protein level. The intronic mutations and most coding region mutations in exon 10 increase the splicing of this exon, changing the ratio between threeand four-repeat isoforms (3, 4). Approximately half of the known mutations have their primary effect at the RNA level. They affect exon splicing enhancer and silencer sequences in exon 10 (8) or destabilize a predicted stem-loop structure located at the boundary between exon 10 and the intron that follows it (3, 4, 9) (Fig. 1b). Thus, to a significant extent, FTDP-17 is a disease of alternative mRNA splicing. The other mutations affect tau isoforms directly. In accordance with their location in the microtubule-binding region, most missense mutations and the deletion mutations lead to a reduced ability of tau to promote microtubule assembly (10, 11). A number of mutations may cause FTDP-17, at least in part, by promoting the assembly of tau into filaments (12, 13). Kraemer et al. (5) expressed the 412-aa isoform of human tau in nerve cells of C. elegans, either in the wildtype form or with a missense mutation of FTDP-17 (P301L or V337M, Fig. 1a). This resulted in a reduced lifespan, behavioral impairment, defective cholinergic neurotransmission, the accumulation of insoluble phosphorylated