Genetics of a Dementia Disorder

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 10

Sep 18, 2000
Karen Young Kreeger

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)

A trio of papers have pinned down a host of mutations responsible for a relatively rare disorder called frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). The disease is characterized by three sets of symptoms: behavioral problems, most frequently disinhibition; cognitive problems, such as memory loss that progresses to full dementia; and movement disorders, most commonly parkinsonism. The first paper discussed here reports six mutations--three missense and three splicing--in 10 families. The other two papers report a single mutation--one a missense mutation, another a single splicing--in a single family. All of these mutations differ from each other.

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."


Gerald D.Schellenberg
Through gene linkage studies and physical mapping, the laboratory of Gerard D. Schellenberg, associate director for research at the Geriatric Research Education and Clinical Center, Veterans Affairs Medical Center in Seattle, identified a causative mutation in one FTDP-17 family. Says Schellenberg regarding his team's contribution, "Subsequently people have looked harder with more sensitive methods, and it's now clear that every family that has a tau mutation has some kind of tau pathology. At the time of our paper's publication, tau was a good candidate but didn't fit perfectly."

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
Maria Grazia Spillantini has been working on tau for 12 years, first with Michel Goedert at the MRC Laboratory of Molecular Biology in Cambridge, United Kingdom, and later in her own lab at the Brain Repair Centre and Department of Neurology at Cambridge University. In the FTDP-17 family that she studied in collaboration with Bernardino Ghetti, Jill Murrell, and Goedert, the group discovered tau deposits that contained filaments with only the four-repeat tau isoforms. To get to the bottom of this, she looked at soluble tau (the tau not contained in the filaments) in samples of affected family members and found that the number of four-repeat tau molecules increased compared with that of normal brain and brain from nonaffected family members. The team speculated that this was likely due to an alteration in exon 10 splicing. Indeed, Spillantini found a splicing mutation, specifically a G to A transition in the nucleic acid sequence of the intron that follows exon 10 of the gene for tau. The mutation disrupts a predicted stem-loop structure, the same structure altered by the splicing mutations identified by the Hutton group, but with different approaches.

"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 (kykreeger@aol.com) is a contributing editor for The Scientist.