| For this article Karen Young Kreeger interviewed Michael Hutton, senior associate consultant, Mayo Clinic, Jacksonville, Fla.; Gerard D. Schellenberg, associate director for research, Geriatric Research Education and Clinical Center, Veterans Affairs Medical Center, Seattle; and Maria Grazia Spillantini, the William Scholl lecturer in neurology, Centre for Brain Repair, Cambridge University, United Kingdom. Data from the Web of Science (ISI, Philadelphia) show that Hot Papers are cited 50 to 100 times more often than the average paper of the same type and age. |
M. Hutton, C.L. Lendon, P. Rizzu, M. Baker, S. Froelich, H. Houlden, S. Pickering-Brown, S. Chakraverty, A. Isaacs, A. Grover, J. Hackett, J. Adamson, S. Lincoln, D. Dickson, P. Davies, R.C. Petersen, M. Stevens, E. de Graff, E. Wauters, J. van Baren, M. Hillebrand, M. Joosse, J.M. Kwon, P. Nowotny, L.K. Che, J.C. Morris, L.A. Reed, J. Trojanowski, H. Basun, L. Lannfelt, M. Neystat, S. Fahn, F. Dark, T. Tannenberg, P.R. Dodd, N. Hayward, J.B.J. Kwok, P.R. Schofield, A. Andreadis, J. Snowden, D. Craufurd, D. Neary, F. Owen, B.A. Oostra, J. Hardy, A. Goate, J. van Swieten, D. Mann, T. Lynch, P. Heutink, "Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17," Nature, 393:702-5, 1998. (Cited in more than 205 papers since publication)
P. Poorkaj, T.D. Bird, E. Wijsman, E. Nemens, R.M. Garruto, L. Anderson, A. Andreadis, W.C. Wiederholt, M. Raskind, G.D. Schellenberg, "Tau is a candidate gene for chromosome 17 frontotemporal dementia," Annals of Neurology, 43:815-25, 1998. (Cited in more than 150 papers since publication)
M.G. Spillantini, J.R. Murrell, M. Goedert, M.R. Farlow, A. Klug, B. Ghetti, "Mutation in the tau gene in familial multiple system tauopathy with presenile dementia," Proceedings of the National Academy of Sciences, 95:7737-41, 1998. (Cited in more than 135 papers since publication)
The laboratory of Michael Hutton, senior associate consultant at the Mayo Clinic in Jacksonville, Fla., and a large consortium of associates reported a series of mutations in the gene that encodes the protein tau. These mutations are connected with frontotemporal dementia that had previously been linked to the region of chromosome 17 that contains the tau gene in certain families. "This is important because the mutations demonstrate that tau dysfunction can lead to neurodegeneration and frontotemporal dementia and by extension provides good evidence that the tau dysfunction we see in Alzheimer's disease almost certainly also contributes to the pathogenesis of that disease," concludes Hutton.
Overall the Hutton team identified three missense mutations and three splicing mutations at the 5' splice site of exon 10. The missense mutations change the sequence of the tau protein. On the other hand, the exon 10 splice site mutations increase the splicing of exon 10 such that there is more exon 10+ RNA, and as a result more tau protein with the extra microtubule-binding domain that is encoded by exon 10.
Some of the missense mutations disrupt an invariant motif in the microtubule- binding repeats, thereby disrupting the interaction of the tau protein and the microtubule. Microtubules are trafficking pathways for macromolecules important in neuron function. Tau binds to microtubules and regulates transport of molecules along them. In the brain there's normally a 1:1 ratio of tau with three microtubule-binding repeats and tau with four microtubule-binding repeats. The exon 10 splice-site mutations increase the proportion by about two- to three-fold of tau with four microtubule-binding repeats.
But how does this cause the neuropathology associated with FTDP-17? "That's the key question," answers Hutton. "What we do know is that in patients that have that type of mutation, we see an increase in tau with the four repeats, but we also see that the tau that's associated with FTDP-17 pathology--the neurofibrillary tangles--is almost entirely the four-repeat tau. It's selectively deposited. What we don't understand is why increasing the amount of four-repeat tau has this effect."
He says that there was also a question of whether tau was really in the region of chromosome 17, as indicated by other linkage studies. "We did a lot of physical mapping for that paper to try to make sure tau was really in the interval bracket as shown by other genetics studies," he recalls. "Tau was in the right place with respect to our families, but not some others. The other confusion was that some people had sequenced some of the other FTDP families and failed to find any tau mutations. The word on the street was that tau wasn't it."
Schellenberg surmises that as a result of his team's work, other groups have now gone back and looked more carefully at their samples and have started to find mutations in tau. He adds that the neurofibrillary tangles seen in the pathology of the FTDP-17 family that he studied are unique in their tau pathology. "This family had tangles that looked exactly like Alzheimer's tangles, which is not true of all tau mutations. What this work shows is that if tau is modified by a mutation, that in and of itself will cause cell death, neurodegeneration, and tangle formation that looks just like that in Alzheimer's disease." However, adds Schellenberg, while the tangles looked like Alzheimer's, there were no amyloid deposits in the family his group studied.
Maria Grazia Spillantini
"This departure from the normal ratio of four-repeat to three-repeat tau leads to the formation of abnormal tau filaments, which accumulate, causing neuronal and glial cell death and eventually the symptoms of FTDP-17," explains Spillantini. "This has important implications for understanding Alzheimer's disease because it shows that tau aggregation by itself can lead to neuronal death and development of disease."
Karen Young Kreeger (email@example.com) is a contributing editor for The Scientist.