Tau Mutations in Neurodegenerative Diseases *

MINIREVIEW Tau Mutations in Neurodegenerative Diseases* Published, JBC Papers in Press, October 22, 2008, DOI 10.1074/jbc.R800013200 Michael S. Wolf...
Author: Mariah Simpson
3 downloads 0 Views 374KB Size

Tau Mutations in Neurodegenerative Diseases* Published, JBC Papers in Press, October 22, 2008, DOI 10.1074/jbc.R800013200

Michael S. Wolfe1 From the Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115

Tau deposition is found in a variety of neurodegenerative brain diseases. The identification of tau mutations that cause familial dementia demonstrated that aberrant Tau alone could cause neurodegenerative disease and suggested that Tau likely plays a role in other cases in which Tau deposits are found, most notably Alzheimer disease. The mechanisms by which tau mutations cause neurodegeneration vary and are unclear to some degree, but evidence supports changes in alternative splicing, phosphorylation state, interaction with tubulin, and selfassociation into filaments as important contributing factors.

Tau Pathology in Alzheimer and Other Neurodegenerative Diseases AD2 is characterized pathologically by extracellular deposits of A␤ and by neurofibrillary tangles and neuropil threads composed of hyperphosphorylated filaments of the otherwise microtubule-associated protein Tau. Although A␤ is apparently the initiator in AD pathogenesis, it has become increasingly clear that aberrant Tau protein also plays a key role (reviewed in Refs. 1 and 2). This role apparently lies downstream of A␤, although the molecular connection between A␤ and Tau is unknown. Tau deposition is seen not only in AD but in a number of other neurodegenerative diseases as well, including frontotemporal dementia, Pick disease, dementia pugilistica, corticobasal degeneration, and progressive supranuclear palsy (reviewed in Refs. 1–3). In these various disorders, collectively called tauopathies, aberrant Tau is the principal pathological feature. Previous debates about the pathogenic role of Tau in these diseases were largely settled with the discovery that mutations in the tau gene itself are associated with a certain form of frontotemporal dementia (4 – 6), strong evidence that changes in the Tau protein alone can cause neurodegeneration. This minireview focuses on the normal biological chemistry of Tau and how disease-associated mutations in tau might lead to neurodegeneration.

* This is the ninth article of eleven in the Thematic Minireview Series on the Molecular Basis of Alzheimer Disease. This minireview will be reprinted in the 2009 Minireview Compendium, which will be available in January, 2010. 1 To whom correspondence should be addressed. E-mail: mwolfe@rics. bwh.harvard.edu. 2 The abbreviations used are: AD, Alzheimer disease; A␤, amyloid ␤-protein; snRNP, small nuclear ribonucleoprotein; SNP, single nucleotide polymorphism; ISS, intron splicing silencer; ESE, exon splicing enhancer.

MARCH 6, 2009 • VOLUME 284 • NUMBER 10

This paper is available online at www.jbc.org THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 284, NO. 10, pp. 6021–6025, March 6, 2009 © 2009 by The American Society for Biochemistry and Molecular Biology, Inc. Printed in the U.S.A.

Normal Tau Function and Isoforms Tau is normally associated with microtubules and is involved in their assembly and stabilization (7, 8). Microtubules are critical for cellular function, especially for neurons, which require microtubule assembly from tubulin building blocks for the growth and integrity of axons and dendrites (reviewed in Ref. 9) and for the transport of molecular cargo between the cell body and distant synapses (reviewed in Ref. 10). Tau plays an important role in microtubule dynamics: too little may destabilize microtubules, and too much may overly stabilize them. Most recently, Tau has been found to be a key player in anterograde transport by kinesin and retrograde transport by the dynein complex (11). The Tau protein undergoes extensive and complex phosphorylation, and the phosphorylation state can affect microtubule binding (reviewed in Ref. 12). Kinase-mediated phosphorylation inhibits microtubule binding, whereas phosphatase-mediated dephosphorylation restores binding. Despite the ostensibly essential function of Tau in microtubule formation, maintenance, and dynamics, tau knock-out mice display only mild phenotypes, including muscle weakness, hyperactivity, and impaired fear conditioning, but not neurodegeneration (13). This suggests that neurodegeneration is not due to simple loss of Tau function. However, compensation during development cannot be ruled out, and a conditional knock-out of tau in the adult mouse brain may provide more definitive answers to the question of whether loss of Tau function alone can contribute to neurodegeneration. Tau is abundantly expressed in the central nervous system, especially in neurons (14), and its role in microtubule formation and function suggests that disruption of microtubules, so critical to axonal structure and transport, may be one way by which aberrant Tau leads to neurodegeneration. The Tau protein contains several imperfectly repeated 18-residue microtubule-binding domains in the C-terminal region (15–17). These are linked through a proline-rich region to an acidic N-terminal region (also called the projection domain) that has recently been shown to interact with the p150 subunit of the dynactin complex involved in retrograde axonal transport (18). In addition to the repeat domains, other regions of the protein may play contributing roles in microtubule binding (e.g. Ref. 19). The tau gene is composed of 16 exons, 11 of which are expressed in the central nervous system, and the pre-mRNA undergoes alternative splicing of exons 2, 3, and 10 (Fig. 1) (20 –22). Exons 2 and 3 each encode 29 amino acids, and the inclusion of exon 2 is coupled to exon 3 inclusion but not vice versa. Thus, Tau isoforms are 2N (both exons 2 and 3), 1N (exon 3 only), or 0N (neither). Exon 10 encodes 31 amino acids and the second of four possible microtubule-binding domains; alternative splicing of exon 10 results in a 4R (with four microtubule-binding domain repeats) or 3R (three repeats) form of Tau (22–24). Thus, altogether six isoforms of Tau are normally expressed in central nervous system neurons. The formation of these isoforms changes during the course of development, with 0N/3R Tau seen solely in the fetal brain and all six isoforms seen normally in the adult brain (24). The 4R/3R ratio, critical to JOURNAL OF BIOLOGICAL CHEMISTRY


MINIREVIEW: Tau Mutations in Neurodegenerative Diseases mutation of a conserved arginine in the N-terminal region has recently been found to disrupt binding to the p150 subunit of the dynactin complex (18). Most of the silent mutations increase the 4R/3R ratio by modulating alternative splicing of exon 10. Missense mutations found within exon 10 affect only the three 4R isoforms, whereas those found outside this region affect all six Tau isoforms. Along with the consistent Tau deposition in these familial cases and the observation that complete knock-out of tau in mice does not lead to neurodegeneration, the fact that all but one of the diseaseassociated mutations (26) are dominant strongly suggests a gain of a toxic function: one normal copy remains, and in the case of exon 10 missense mutations, even the 3R Tau translated from the disease allele is normal. No disease-associated mutations that lead to either a truncated protein or the nonsenseFIGURE 1. Six isoforms of the Tau protein found in the central nervous system that result from alternative mediated decay of message have splicing of exons 2, 3, and 10. Exons 9 –12 encode regions that include imperfectly repeated microtubule- been identified. binding domains. Missense mutations that are associated with familial FTDP-17T and related disorders are Differences in the clinical and labeled in the longest Tau isoform (2N/4R). Red mutations are also associated with changes in exon 10 alternative splicing. Note that mutations located within exon 10 would be translated only into 4R Tau isoforms. The pathological phenotypes are seen asterisk indicates a single example of a lethal recessive tau mutation, which presented as respiratory hypovenbetween the various tau mutations tilation and displayed neuronal Tau pathology (26). (reviewed in Refs. 3 and 25). Although many mutations lead to a disease pathogenesis (see below), is roughly 1:1 in the adult phenotype resembling FTDP-17T, others lead to phenotypes overlapping or identical to Pick disease, corticobasal degenerabrain. tion, progressive supranuclear palsy, or AD. Some mutations Mutations in FTDP-17 lead to Tau pathology in both neurons and glial cells, whereas The understanding of the role of aberrant Tau in neurode- others lead to Tau pathology primarily or strictly in neurons. generative diseases was dramatically advanced in 1998 when However, rather than suggesting specific phenotypic differmutations in the tau gene were discovered to be associated with ences between tau mutations, many of these differences may FTDP-17T (frontotemporal dementia with parkinsonism reflect the different genetic and environmental contexts in linked to chromosome 17 and specifically characterized by tau which these mutations happen to reside. Ultrastructural differpathology) (4 – 6). Initially identified mutations cluster in and ences in Tau filaments in brain tissue are also observed between around the regions encoding the microtubule-binding different tau mutations, with some correlating with twisted heldomains, suggesting that perturbed ability to bind microtu- ical filaments, some with paired helical filaments (similar to bules might be involved in neuronal destruction and death in what is seen in AD), and still others with straight filaments (25). these families. The FTDP-17T mutations provided clear evi- How these mutations may lead to differently assembled Tau dence that alterations in tau alone could cause neurodegenera- filaments is unclear, especially because no high resolution tive disease and strongly suggested that aberrant Tau plays a structure of Tau or Tau mutants is available. pathogenic role in other tauopathies, including AD. To date, at least 37 mutations associated with FTDP-17T or Mutations That Affect Splicing related disorders have been identified (Figs. 1 and 2) (reviewed Roughly half of the identified tau mutations associated with in Ref. 25). These are all missense mutations, mutations that FTDP-17 affect the alternative splicing of exon 10 (reviewed in affect splicing, or both, and almost all cluster in the portion Refs. 3 and 25). Although a number of these are intronic mutaencoding the C-terminal region or in an intervening sequence tions near the exon 10 5⬘-splice site, others are mutations in the near exon 10. The C-terminal missense mutations all appear to coding region of exon 10. Almost all of these mutations lead to impair Tau binding to microtubules and the ability of Tau to an increased inclusion of exon 10 and therefore an increase in promote microtubule assembly, whereas a disease-associated the 4R/3R ratio. However, three mutations apparently do the


VOLUME 284 • NUMBER 10 • MARCH 6, 2009

MINIREVIEW: Tau Mutations in Neurodegenerative Diseases seventh base pair. The structure further shows that this unpaired purine ring is intercalated back into the A-form RNA duplex. Disease-associated mutations would be predicted to destabilize the stem-loop and make this site more available to splicing factors (specifically the U1 snRNP that interacts with 5⬘-splice sites; see Fig. 2). Thermal stability studies of oligonucleotides demonstrated that disease-associated mutations within the putative stem-loop lower the melting temperature of the RNA duplex (i.e. where the double-stranded RNA dissociates to the single-stranded form) (30, 31). A minigene construct encoding exons 9 –11 recapitulated normal Tau exon 10 splicing for the wild-type sequence and increased exon 10 inclusion for disease-causing mutations (32). This minigene has been used to demonstrate that other mutations specifically designed to enhance stability of the stem-loop (and located FIGURE 2. FTDP-17 mutations located near the exon 10-intron 10 interface. Exonic sequences are in black and uppercase; intronic sequences are in red and lowercase. Eight mutations destabilize a stem-loop located at distal to the U1 snRNP-binding site) the exon-intron border (upper) that apparently regulates interaction with the U1 snRNP splicing factor (lower). reduce exon 10 inclusion to decrease Two mutations (S305N and exons 10 ⫹ 3 (Ex10⫹3)) also stabilize the interaction of Tau pre-mRNA with U1 the 4R/3R ratio as predicted (31). snRNP. The double asterisks indicate disease-causing mutations that enhance interaction with U1 snRNP. Other evidence has been taken to opposite, inhibiting inclusion of exon 10 and decreasing the suggest that the stem-loop is not a biologically relevant struc4R/3R ratio, suggesting that perhaps the 3R/4R balance is crit- ture and that these intronic mutations instead either enhance the complementarity of the 5⬘-splice site with the U1 SNP or ical (27, 28). The silent and intronic mutations that increase 4R Tau affect an ISS and the binding of a repressor protein (27, 33, 34). would be expected to have the opposite effect on microtubule However, U1 SNP complementarity changes cannot explain binding to most of the missense mutations: the former would the effects of all the mutations in this region, an ISS cannot lead to increased binding, whereas the latter would decrease explain the effects of stem-loop-stabilizing mutations, and no binding. How then can both types of mutations lead to fila- protein factor involved in ISS recognition has been identified. Other disease-causing mutations outside the stem-loop can ments of hyperphosphorylated Tau? One idea is that the increase in 4R Tau saturates the binding sites on microtubules also increase exon 10 splicing, likely due to strengthening of an and thereby results in unassociated 4R Tau that is more prone ESE or weakening of an ISS or an exon splicing silencer. Putato phosphorylation and self-assembly (25). Another possibility tive ESE regions have been identified in exon 10 (33, 35), with is that higher association with microtubules may create higher one being a purine-rich ESE and where mutations N279K and local concentrations of 4R Tau and therefore a better microen- ⌬K280 reside. The splicing factor Tra2␤, part of a class of RNAvironment for assembly. In cases in which mutations shift in binding proteins that contain serine- and arginine-rich favor of 3R Tau, less binding to microtubules is thought to domains, binds to this purine-rich ESE to enhance exon 10 increase the cytosolic concentration of Tau and favor inclusion (35). In addition, an intron silencer modulator self-association. sequence element has been identified just downstream of the The silent and intronic mutations near the exon 10 5⬘-splice stem-loop, and this element contains the ⫹19 mutation that site enhance exon 10 inclusion through two general mecha- increases 3R Tau (34). nisms: altering linear cis-splicing elements or destabilizing a stem-loop structure at the exon-intron junction. The stem- Missense Mutations That Affect Protein-Protein loop structure was hypothesized (4, 6, 29) upon the initial dis- Interactions covery of FTDP-17 mutations in the tau gene, noting the apparOther missense mutations apparently decrease the ability of ent self-complementarity in this region. Subsequent Tau to facilitate microtubule assembly. These mutations are determination of the solution structure of an oligonucleotide found primarily in and around the microtubule-binding based on this exon-intron junction by NMR spectroscopy (30) domains and reduce the ability of Tau to promote microtubule led to refinement of the stem-loop model to seven specific base assembly from tubulin (36, 37). Two exceptions are S305N and pairs (Fig. 2), with an adenosine bulge between the sixth and Q336R, which enhance the ability of Tau to facilitate microtuMARCH 6, 2009 • VOLUME 284 • NUMBER 10



MINIREVIEW: Tau Mutations in Neurodegenerative Diseases bule assembly (38, 39). The S305N mutation alters exon 10 splicing (27); thus, distinguishing the mechanism by which this mutation exerts pathogenicity is difficult. However, the ability of the Q336R mutation to enhance the microtubule binding role of Tau again suggests that the balance of Tau proteins capable of interacting with microtubules may be a critical factor ultimately dictating whether Tau will self-assemble into filaments or not. Other evidence suggests that missense mutations may directly confer the ability of Tau to form filaments. Some studies show for instance that a wide range of missense mutants (R5L, K257T, I260V, G272V, ⌬K280, P301L, P301S, G335V, Q336R, V337M, and R406W) promote in vitro formation of filaments in the presence of polymerization-inducing agents such as heparin and arachidonic acid (39 – 46). Filament formation has also been observed in neuroglioma cells upon expression of mutant Tau (47). Phosphorylation is also thought to be critical to the pathogenicity of Tau (reviewed in Ref. 12). Tau is phosphorylated in multiple sites by multiple kinases, but some sites tend to be more phosphorylated in Tau pathology. Studying the role of these phosphorylations in tauopathies is fraught with difficulties, however. In vitro phosphorylations by particular kinases are typically challenging to confirm in vivo, and the order of events (phosphorylation vis-a`-vis microtubule dissociation or filament formation) is still unclear. Some kinase inhibitors have been shown to dramatically reduce Tau pathology in transgenic mice (48, 49), but such agents notoriously lack specificity. Nevertheless, some evidence has been reported that disease-associated Tau missense mutations can lead to enhanced phosphorylation (50), and hyperphosphorylation can induce Tau self-assembly into filaments (51). Other studies show that Tau mutants bind less to phosphatase 2A (52), the principal phosphatase in the brain, which associates with the microtubule-binding repeat domains.

Animal Models A number of transgenic mice expressing Tau have been developed to generate disease models for tauopathies, and some show Tau pathology and neurodegeneration as well as behavioral deficits (reviewed in Ref. 2; also see minireview by Morrissette et al. (61) on AD mouse models in this series). These mice have provided critical in vivo models for determining the role of aberrant Tau in neurodegeneration. For instance, evidence suggests that microgliosis and synaptic pathology may be the earliest manifestation of neurodegenerative tauopathies and that abrogation of Tau-induce microglial activation may be therapeutically beneficial (53). A mouse line expressing human genomic tau expresses all six brain isoforms of Tau and allows the study of the splicing of human Tau in vivo (54). Crossing tau transgenic mice with those that overproduce A␤ has provided important models for AD that have shed light on the role of Tau with respect to A␤ (55). Moreover, knock-out of endogenous mouse tau alleviates A␤-induced memory deficits (56), suggesting that targeting Tau may be a worthwhile AD therapeutic strategy. Questions remain regarding the pathological role of Tau filaments in neurodegeneration. Although most transgenic tau mice suggest that filament formation is connected to neurodegeneration, results with a mouse line containing an inducible


tau gene showed that suppressing Tau improved memory even though neurofibrillary tangles continued to grow (57). One important caveat to this study is that Tau levels under suppressed conditions in these mice were still dramatically higher than those in wild-type mice. Other evidence in flies and worms suggests that Tau can cause neurodegeneration in the absence of filament formation (58, 59). Nevertheless, it would be surprising if Tau filaments within neuronal cell bodies and along axonal and dendritic projections are compatible with normal neuronal function and health.

Haplotypes Although tau mutations have not been identified in neurodegenerative diseases other than familial FTDP-17T, evidence suggests that mutations in the tau gene may nevertheless contribute to the development of other tauopathies (reviewed in Ref. 60). More broadly, the human population has two main tau haplotypes, H1 and H2, which are defined by a set of SNPs and a 238-bp deletion in intron 9. The H2 haplotype is also associated with an inversion of an ⬃900-kb region that includes the entire tau gene. Despite these nucleotide sequence differences, the two haplotypes encode identical protein sequences. The association of certain tau haplotypes with neurodegenerative diseases has been equivocal, however. Conclusions Aberrant Tau clearly plays a role in the pathogenesis of a variety of neurodegenerative brain diseases, and the study of disease-causing mutations in the tau gene has suggested molecular mechanisms. Some mutations reveal that changes in alternative pre-mRNA splicing of exon 10 alone can cause Tau pathology and disease, whereas others point to increased phosphorylation, altered microtubule binding, microtubule instability, and Tau filament formation. Key questions remain, such as how altered microtubule binding leads to Tau filaments, whether microtubule instability alone contributes to neurodegeneration, what cellular pathways might affect Tau splicing, what phosphorylation sites are critical to pathogenesis, what are the key kinases, and what aggregated forms of Tau mediate neurodegeneration. Answers to such questions may reveal new strategies and targets for the treatment of Alzheimer disease and other tauopathies. REFERENCES 1. Goedert, M., and Spillantini, M. G. (2006) Science 314, 777–781 2. Ballatore, C., Lee, V. M., and Trojanowski, J. Q. (2007) Nat. Rev. Neurosci. 8, 663– 672 3. Lee, V. M., Goedert, M., and Trojanowski, J. Q. (2001) Annu. Rev. Neurosci. 24, 1121–1159 4. Hutton, M., Lendon, C. L., Rizzu, P., Baker, M., Froelich, S., Houlden, H., Pickering-Brown, S., Chakraverty, S., Isaacs, A., Grover, A., Hackett, J., Adamson, J., Lincoln, S., Dickson, D., Heutink, P., et al. (1998) Nature 393, 702–705 5. Poorkaj, P., Bird, T. D., Wijsman, E., Nemens, E., Garruto, R. M., Anderson, L., Andreadis, A., Wiederholt, W. C., Raskind, M., and Schellenberg, G. D. (1998) Ann. Neurol. 43, 815– 825 6. Spillantini, M. G., Murrell, J. R., Goedert, M., Farlow, M. R., Klug, A., and Ghetti, B. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 7737–7741 7. Weingarten, M. D., Lockwood, A. H., Hwo, S. Y., and Kirschner, M. W. (1975) Proc. Natl. Acad. Sci. U. S. A. 72, 1858 –1862

VOLUME 284 • NUMBER 10 • MARCH 6, 2009

MINIREVIEW: Tau Mutations in Neurodegenerative Diseases 8. Cleveland, D. W., Hwo, S. Y., and Kirschner, M. W. (1977) J. Mol. Biol. 116, 207–225 9. Dent, E. W., and Gertler, F. B. (2003) Neuron 40, 209 –227 10. Guzik, B. W., and Goldstein, L. S. (2004) Curr. Opin. Cell Biol. 16, 443– 450 11. Dixit, R., Ross, J. L., Goldman, Y. E., and Holzbaur, E. L. (2008) Science 319, 1086 –1089 12. Johnson, G. V., and Stoothoff, W. H. (2004) J. Cell Sci. 117, 5721–5729 13. Ikegami, S., Harada, A., and Hirokawa, N. (2000) Neurosci. Lett. 279, 129 –132 14. Binder, L. I., Frankfurter, A., and Rebhun, L. I. (1985) J. Cell Biol. 101, 1371–1378 15. Himmler, A., Drechsel, D., Kirschner, M. W., and Martin, D. W., Jr. (1989) Mol. Cell. Biol. 9, 1381–1388 16. Lee, G., Neve, R. L., and Kosik, K. S. (1989) Neuron 2, 1615–1624 17. Butner, K. A., and Kirschner, M. W. (1991) J. Cell Biol. 115, 717–730 18. Magnani, E., Fan, J., Gasparini, L., Golding, M., Williams, M., Schiavo, G., Goedert, M., Amos, L. A., and Spillantini, M. G. (2007) EMBO J. 26, 4546 – 4554 19. Goode, B. L., and Feinstein, S. C. (1994) J. Cell Biol. 124, 769 –782 20. Neve, R. L., Harris, P., Kosik, K. S., Kurnit, D. M., and Donlon, T. A. (1986) Brain Res. 387, 271–280 21. Goedert, M., Wischik, C. M., Crowther, R. A., Walker, J. E., and Klug, A. (1988) Proc. Natl. Acad. Sci. U. S. A. 85, 4051– 4055 22. Andreadis, A., Brown, W. M., and Kosik, K. S. (1992) Biochemistry 31, 10626 –10633 23. Goedert, M., Spillantini, M. G., Jakes, R., Rutherford, D., and Crowther, R. A. (1989) Neuron 3, 519 –526 24. Goedert, M., Spillantini, M. G., Potier, M. C., Ulrich, J., and Crowther, R. A. (1989) EMBO J. 8, 393–399 25. Goedert, M., and Jakes, R. (2005) Biochim. Biophys. Acta 1739, 240 –250 26. Nicholl, D. J., Greenstone, M. A., Clarke, C. E., Rizzu, P., Crooks, D., Crowe, A., Trojanowski, J. Q., Lee, V. M., and Heutink, P. (2003) Ann. Neurol. 54, 682– 686 27. D’Souza, I., Poorkaj, P., Hong, M., Nochlin, D., Lee, V. M., Bird, T. D., and Schellenberg, G. D. (1999) Proc. Natl. Acad. Sci. U. S. A. 96, 5598 –5603 28. Stanford, P. M., Shepherd, C. E., Halliday, G. M., Brooks, W. S., Schofield, P. W., Brodaty, H., Martins, R. N., Kwok, J. B., and Schofield, P. R. (2003) Brain 126, 814 – 826 29. Grover, A., Houlden, H., Baker, M., Adamson, J., Lewis, J., Prihar, G., Pickering-Brown, S., Duff, K., and Hutton, M. (1999) J. Biol. Chem. 274, 15134 –15143 30. Varani, L., Hasegawa, M., Spillantini, M. G., Smith, M. J., Murrell, J. R., Ghetti, B., Klug, A., Goedert, M., and Varani, G. (1999) Proc. Natl. Acad. Sci. U. S. A. 96, 8229 – 8234 31. Donahue, C. P., Muratore, C., Wu, J. Y., Kosik, K. S., and Wolfe, M. S. (2006) J. Biol. Chem. 281, 23302–23306 32. Jiang, Z., Cote, J., Kwon, J. M., Goate, A. M., and Wu, J. Y. (2000) Mol. Cell. Biol. 20, 4036 – 4048 33. D’Souza, I., and Schellenberg, G. D. (2000) J. Biol. Chem. 275, 17700 –17709 34. D’Souza, I., and Schellenberg, G. D. (2002) J. Biol. Chem. 277, 26587–26599 35. Jiang, Z., Tang, H., Havlioglu, N., Zhang, X., Stamm, S., Yan, R., and Wu, J. Y. (2003) J. Biol. Chem. 278, 18997–19007 36. Hong, M., Zhukareva, V., Vogelsberg-Ragaglia, V., Wszolek, Z., Reed, L., Miller, B. I., Geschwind, D. H., Bird, T. D., McKeel, D., Goate, A., Morris, J. C., Wilhelmsen, K. C., Schellenberg, G. D., Trojanowski, J. Q., and Lee, V. M. (1998) Science 282, 1914 –1917 37. Hasegawa, M., Smith, M. J., and Goedert, M. (1998) FEBS Lett. 437, 207–210

MARCH 6, 2009 • VOLUME 284 • NUMBER 10

38. Hasegawa, M., Smith, M. J., Iijima, M., Tabira, T., and Goedert, M. (1999) FEBS Lett. 443, 93–96 39. Pickering-Brown, S. M., Baker, M., Nonaka, T., Ikeda, K., Sharma, S., Mackenzie, J., Simpson, S. A., Moore, J. W., Snowden, J. S., de Silva, R., Revesz, T., Hasegawa, M., Hutton, M., and Mann, D. M. (2004) Brain 127, 1415–1426 40. Nacharaju, P., Lewis, J., Easson, C., Yen, S., Hackett, J., Hutton, M., and Yen, S. H. (1999) FEBS Lett. 447, 195–199 41. Goedert, M., Jakes, R., and Crowther, R. A. (1999) FEBS Lett. 450, 306 –311 42. Gamblin, T. C., King, M. E., Dawson, H., Vitek, M. P., Kuret, J., Berry, R. W., and Binder, L. I. (2000) Biochemistry 39, 6136 – 6144 43. Barghorn, S., Zheng-Fischhofer, Q., Ackmann, M., Biernat, J., von Bergen, M., Mandelkow, E. M., and Mandelkow, E. (2000) Biochemistry 39, 11714 –11721 44. von Bergen, M., Barghorn, S., Li, L., Marx, A., Biernat, J., Mandelkow, E. M., and Mandelkow, E. (2001) J. Biol. Chem. 276, 48165– 48174 45. Grover, A., England, E., Baker, M., Sahara, N., Adamson, J., Granger, B., Houlden, H., Passant, U., Yen, S. H., DeTure, M., and Hutton, M. (2003) Exp. Neurol. 184, 131–140 46. Neumann, M., Diekmann, S., Bertsch, U., Vanmassenhove, B., Bogerts, B., and Kretzschmar, H. A. (2005) Neurogenetics 6, 91–95 47. DeTure, M., Ko, L. W., Easson, C., and Yen, S. H. (2002) Am. J. Pathol. 161, 1711–1722 48. Noble, W., Planel, E., Zehr, C., Olm, V., Meyerson, J., Suleman, F., Gaynor, K., Wang, L., LaFrancois, J., Feinstein, B., Burns, M., Krishnamurthy, P., Wen, Y., Bhat, R., Lewis, J., Dickson, D., and Duff, K. (2005) Proc. Natl. Acad. Sci. U. S. A. 102, 6990 – 6995 49. Le Corre, S., Klafki, H. W., Plesnila, N., Hubinger, G., Obermeier, A., Sahagun, H., Monse, B., Seneci, P., Lewis, J., Eriksen, J., Zehr, C., Yue, M., McGowan, E., Dickson, D. W., Hutton, M., and Roder, H. M. (2006) Proc. Natl. Acad. Sci. U. S. A. 103, 9673–9678 50. Alonso, A. d. C., Mederlyova, A., Novak, M., Grundke-Iqbal, I., and Iqbal, K. (2004) J. Biol. Chem. 279, 34873–34881 51. Alonso, A., Zaidi, T., Novak, M., Grundke-Iqbal, I., and Iqbal, K. (2001) Proc. Natl. Acad. Sci. U. S. A. 98, 6923– 6928 52. Goedert, M., Satumtira, S., Jakes, R., Smith, M. J., Kamibayashi, C., White, C. L., III, and Sontag, E. (2000) J. Neurochem. 75, 2155–2162 53. Yoshiyama, Y., Higuchi, M., Zhang, B., Huang, S. M., Iwata, N., Saido, T. C., Maeda, J., Suhara, T., Trojanowski, J. Q., and Lee, V. M. (2007) Neuron 53, 337–351 54. Duff, K., Knight, H., Refolo, L. M., Sanders, S., Yu, X., Picciano, M., Malester, B., Hutton, M., Adamson, J., Goedert, M., Burki, K., and Davies, P. (2000) Neurobiol. Dis. 7, 87–98 55. Oddo, S., Billings, L., Kesslak, J. P., Cribbs, D. H., and LaFerla, F. M. (2004) Neuron 43, 321–332 56. Roberson, E. D., Scearce-Levie, K., Palop, J. J., Yan, F., Cheng, I. H., Wu, T., Gerstein, H., Yu, G. Q., and Mucke, L. (2007) Science 316, 750 –754 57. Santacruz, K., Lewis, J., Spires, T., Paulson, J., Kotilinek, L., Ingelsson, M., Guimaraes, A., DeTure, M., Ramsden, M., McGowan, E., Forster, C., Yue, M., Orne, J., Janus, C., Mariash, A., Kuskowski, M., Hyman, B., Hutton, M., and Ashe, K. H. (2005) Science 309, 476 – 481 58. Wittmann, C. W., Wszolek, M. F., Shulman, J. M., Salvaterra, P. M., Lewis, J., Hutton, M., and Feany, M. B. (2001) Science 293, 711–714 59. Kraemer, B. C., Zhang, B., Leverenz, J. B., Thomas, J. H., Trojanowski, J. Q., and Schellenberg, G. D. (2003) Proc. Natl. Acad. Sci. U. S. A. 100, 9980 –9985 60. Pittman, A. M., Fung, H. C., and de Silva, R. (2006) Hum. Mol. Genet. 15, R188 –R195 61. Morrissette, D. A., Parachikova, A., Green, K. N., and LaFerla, F. M. (2009) J. Biol. Chem. 284, 6033– 6037



Suggest Documents