Filamentous nerve cell inclusions in neurodegenerative diseases

Current Opinion in Neurobiology

Volumn 8, Issue 5, 1998, Pages 619-632

  Goedert, Michel ^a   Spillantini, Maria Grazia ^b   Davies, Stephen W ^b,c  

^a MRC LABORATORY OF MOLECULAR BIOLOGY   (United Kingdom)

^b UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^c UNIVERSITY COLLEGE LONDON   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

GLUTAMINE; MICROTUBULE ASSOCIATED PROTEIN; TAU PROTEIN;

ALZHEIMER DISEASE; ATROPHY; CELL INCLUSION; DEGENERATIVE DISEASE; DEMENTIA; DIFFUSE LEWY BODY DISEASE; FAMILIAL DISEASE; GENE MUTATION; HUMAN; HUMAN TISSUE; HUNTINGTON CHOREA; NERVE CELL; NEUROFILAMENT; PARKINSON DISEASE; PRIORITY JOURNAL; REVIEW; TRINUCLEOTIDE REPEAT;

EID: 0032191105     PISSN: 09594388     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0959-4388(98)80090-1     Document Type: Article

References (92)

1. of special interest Hyman BT, Trojanowski JQ. Consensus recommendations for the postmortem diagnosis of Alzheimer disease from the National Institute on Aging and the Reagan Institute working on diagnostic criteria for the neuropathological assessment of Alzheimer disease. J Neuropathol Exp Neurol. 56:1997;1095-1097 This editorial summarises the recommendations made by a panel of distinguished neuropathologists, attempting to improve the postmortem diagnostic criteria for Alzheimer's disease. Neurofibrillary tangels are an essential diagnostic feature, and preclinical Alzheimer's disease is recognised as a neuropathological entity.
2. Selkoe DJ. Cellular and molecular biology of the beta-amyloid precursor protein and Alzheimer's disease. Rosenberg RN, Prusiner SB, DiMauro S, Barchi RL. edn 2 The Molecular and Genetic Basis of Neurological Disease. 1997;601-611 Butterworth-Heinemann, Boston.
3. Goedert M, Trojanowski JQ. The neurofibrillary pathology of Alzheimer's disease. Lee VMY, Rosenberg RN, Prusiner SB, DiMauro S, Barchi RL. edn 2 The Molecular and Genetic Basis of Neurological Disease. 1997;613-627 Butterworth-Heinemann, Boston.
4. of special interest Schmidt ML, Lee VMY, Forman M, Chiu TS, Trojanowski JQ. Monoclonal antibodies to a 100-kd protein reveal abundant Aβ-negative plaques throughout gray matter of Alzheimer's disease brains. Am J Pathol. 151:1997;69-80 This paper reports the unexpected discovery of a new type of extracellular deposit in Alzheimer's disease brain. Four monoclonal antibodies raised against neurofibrillary lesion-enriched fractions from Alzheimer's disease brain were found not to react with hyperphosphorylated tau protein or Aβ. Instead, they stained an abundant extracellular plaque-like pathology distinct from the Aβ pathology. On immunoblots, a protein of approximately 100 kDa was recognised by these antibodies.
5. of special interest Harper JD, Wong SD, Lieber CM, Lansbury PT. Observation of metastable Aβ amyloid protofibrils by atomic force microscopy. Chem Biol. 4:1997;119-125 See annotation [6].
6. of special interest Walsh DM, Lomakin A, Benedek G, Condron MM, Teplow DB. Amyloid β-protein fibrillogenesis. Detection of a protofibrillar intermediate. J Biol Chem. 272:1997;22364-22372 These papers [5,6] identify a metastable protofibril intermediate in the formation of Aβ amyloid fibrils in vitro. The possibility is raised that diffuse amyloid deposits in brain may consist of such protofibrils.
7. Kurochkin IV, Goto S. Alzheimer's β-amyloid peptide specifically interacts with and is degraded by insulin degrading enzyme. FEBS Lett. 34:1994;33-37.
8. McDermott JR, Gibson AM. Degradation of Alzheimer's beta-amyloid protein by human and rat brain peptidases: involvement of insulin-degrading enzyme. Neurochem Res. 22:1997;49-56.
9. Drewes G, Ebneth A, Preuss U, Mandelkow EM, Mandelkow E. MARK, a novel family of protein kinases that phosphorylate microtubule-associated proteins and trigger microtubule disruption. Cell. 89:1997;297-308.
10. Reynolds CH, Utton MA, Gibb GM, Yates A, Anderton BH. Stress-activated protein kinase/c-Jun N-terminal kinase phosphorylates tau protein. J Neurochem. 68:1997;1736-1744.
11. Goedert M, Hasegawa M, Jakes R, Lawler S, Cuenda A, Cohen P. Phosphorylation of microtubule-associated protein tau by stress-activated protein kinases. FEBS Lett. 409:1997;57-62.
12. of special interest Munoz-Montano JR, Moreno FJ, Avila J, Diaz-Nido J. Lithium inhibits Alzheimer's disease-like tau protein phosphorylation in neurons. FEBS Lett. 411:1997;183-188 Using cultured cerebellar granule cells treated with lithium chloride to inhibit glycogen synthase kinase-3 (GSK3), the authors show a reduction in the phosphorylation of tau protein. Moreover, they observe a similar effect in rat brain upon peripheral injection of lithium chloride. Assuming that lithium chloride is a specific inhibitor of GSK3 at the doses used, this work establishes that GSK3 is a tau kinase in normal brain.
13. of special interest Hong M, Chen DCR, Klein PS, Lee VM-Y. Lithium reduces tau phosphorylation by inhibition of glycogen synthase kinase-3. J Biol Chem. 272:1997;25326-25332 Using cultured NT2N neurones, the authors demonstrate that lithium chloride reduces the phosphorylation of tau protein, resulting in increased binding to microtubules and enhanced microtubule assembly.
14. Goedert M, Jakes R, Spillantini MG, Hasegawa M, Smith MJ, Crowther RA. Assembly of microtubule-associated protein tau into Alzheimer-like filaments induced by sulphated glycosaminoglycans. Nature. 383:1996;550-553.
15. Perez M, Valpuesta JM, Medina M, Montejo de Garcini E, Avila J. Polymerization of tau into filaments in the presence of heparin: the minimal sequence required for tau-tau interaction. J Neurochem. 67:1996;1183-1190.
16. Kampers T, Friedhoff P, Biernat J, Mandelkow EM, Mandelkow E. RNA stimulates aggregation of microtubule-associated protein tau into Alzheimer-like paired helical filaments. FEBS Lett. 399:1996;344-349.
17. Arrasate M, Perez M, Valpuesta JM, Avila J. Role of glycosaminoglycans in determining the helicity of paired helical filaments. Am J Pathol. 151:1997;1115-1122.
18. of special interest Hasegawa M, Crowther RA, Jakes R, Goedert M. Alzheimer-like changes in microtubule-associated protein tau induced by sulfated glycosaminoglycans. Inhibition of microtubule binding, stimulation of phosphorylation, and filament assembly depend on the degree of sulfation. J Biol Chem. 272:1997;33118-33124 A detailed study investigating the effects of a number of naturally occurring and synthetic glycosaminoglycans on tau filament assembly, stimulation of tau phosphorylation by mitogen-activated protein kinase, glycogen synthase kinase-3 and neuronal cdc2-like kinase, microtubule binding of tau, and microtubule assembly. The magnitude of the glycosaminoglycan effects was dependent on their degree of sulphation. These in vitro interactions reproduced the known characteristics of paired helical filament tau from Alzheimer's disease brain.
19. Qi Z, Zhu X, Goedert M, Fujita DJ, Wang JH. Effect of heparin on phosphorylation site specificity of neuronal Cdc2-like kinase. FEBS Lett. 423:1998;227-230.
20. Hardy J. Amyloid, the presenilins and Alzheimer's disease. Trends Neurosci. 20:1997;154-159.
21. Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. 375:1995;754-760.
22. Price DL, Sisodia SS. Mutant genes in familial Alzheimer's disease and transgenic models. Annu Rev Neurosci. 21:1998;479-505.
23. Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, Bird TD, Hardy J, Hutton M, Kukull W, et al. Secreted mayloid β-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nat Genet. 2:1996;864-870.
24. of special interest Wild-Bode C, Yamazaki T, Capell A, Leimer U, Steiner H, Ihara Y, Haass C. Intracellular generation and accumulation of amyloid β-peptide terminating at amino acid 42. J Biol Chem. 272:1997;16085-16088 See annotation [26].
25. of special interest Hartmann T, Bieger SC, Brühl B, Tienari PT, Ida N, Allsop D, Roberts GW, Masters CL, Dotti CG, Unsicker K, Beyereuther K. Distinct sites of intracellular production for Alzheimer's disease Aβ40/42 amyloid peptides. Nat Med. 3:1997;1016-1021 See annotation [26].
26. of special interest Cook DG, Forman MS, Sung JC, Leight S, Kolson DL, Iwatsubo T, Lee VM-Y, Doms RW. Alzheimer's Aβ(1-42) is generated in the endoplasmic reticulum/intermediate compartment of NT2N cells. Nat Med. 3:1997;1021-1023 Using a variety of different techniques, these three studies [24-26] demonstrate that Aβ(1-20) and Aβ(1-42) are produced in different cellular compartments. The endoplasmic reticulum is shown to be the site of production of Aβ(1-42). This is consistent with the effects of presenilins on APP processing, because presenilins are also located mainly in the endoplasmic reticulum. It is proposed that increased production of Aβ(1-42) in the endoplasmic reticulum may be the earliest pathological change in the series of events that lead to Alzheimer's disease.
27. of special interest Borchelt DR, Ratovitski T, van Lare J, Lee MK, Gonzales V, Jenkins NA, Copeland NG, Price DL, Sisodia SS. Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor protein. Neuron. 19:1997;939-945 Mice doubly transgenic for A246E PS1 and K670NM671L amyloid precursor protein (APP) are shown to develop Aβ amyloid deposits much earlier than mice transgenic for K670NM671L APP alone. Mice transgenic for A246E PS1 show no overt pathology. See also [28].
28. of special interest Holcomb L, Gordon MN, McGowan E, Yu X, Benkovic S, Jantzen P, Wright K, Saad I, Mueller R, Morgan D, et al. Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med. 4:1998;97-100 Mice doubly transgenic for M146L PS1 and K670NM671L amyloid precursor protein (APP) are shown to develop Aβ deposits much earlier than mice transgenic for K670NM671L APP alone. Mice transgenic for M146L PS1 show no overt pathology. See also [27].
29. of outstanding interest De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, Von Figura K, Van Leuven F. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature. 391:1998;387-390 Neuronal cells cultured from mice deficient in the expression of PS1 were shown to be unable to generate the carboxy-terminal γ-secretase cleavage of the amyloid precursor protein (APP) that gives rise to Aβ(1-42). One function of PS1 is, therefore, to facilitate the proteolytic cleavage of membrane-bound APP. The α- and β -secretase cleavages were unaffected. PS1 is probably not the γ-secretase itself, but may function as a regulatory cofactor in amyloid precursor processing.
30. Struhl G, Adachi A. Nuclear access and action of Notch in vivo. Cell. 93:1998;649-660.
31. Greenwald I. LIN-12/Notch signalling: lessons from worms and flies. Genes Dev. 12:1998;1751-1762.
32. Mayeux R, Saunders AN, Shea S, Mirra S, Evans D, Roses AD, Hyman BT, Crain B, Tang MX, Phelps CH. Utility of the apolipoprotein E genotype in the diagnosis of Alzheimer's disease. N Engl J Med. 338:1998;506-511.
33. Schmechel DE, Saunders AM, Strittmatter WJ, Crain B, Hulette C, Joo SH, Pericak-Vance MA, Goldgaber D, Roses AD. Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease. Proc Natl Acad Sci USA. 90:1993;9649-9653.
34. of special interest Irizarry MC, Soriano F, McNamara M, Page KJ, Schenk D, Games D, Hyman BT. Aβ deposition is associated with neuropil changes, but not with overt neuronal loss in the human amyloid precursor protein V717F (PDAPP) transgenic mouse. J Neurosci. 17:1997;7053-7059 See annotation [35].
35. Sw transgenic mice develop age-related Aβ deposits and neuropil abnormalities, but no neuronal loss in CA1. J Neuropathol Exp Neurol. 56:1997;965-973 These two papers [34,35] show that in two widely used mouse models of Aβ depositon there is no filamentous tau pathology or neuronal cell loss, up to 18 months of age.
36. of special interest Bales KL, Verina T, Dodel RC, Du Y, Altstiel L, Bender M, Hyslop P, Johnstone EM, Little SP, Cummins D, et al. Lack of apolipoprotein E dramatically reduces amyloid β-peptide deposition. Nat Genet. 17:1997;263-264 Mice transgenic for V717F amyloid precursor protein (APP) were crossed into an apoE null background. This resulted in a very significant decrease in their Aβ amyloid load.
37. of special interest Van Leeuwen FW, de Kleijn DPV, van den Hurk HH, Neubauer A, Sonnemans MAF, Sluijs JA, Köycü S, Ramdjielal RDJ, Salehi A, Martens GJM, et al. Frameshift mutants of β amyloid precursor protein and ubiquitin-B in Alzheimer's and Down patients. Science. 279:1998;242-247 The authors used PCR to identify frame-shifted transcripts encoding amyloid precursor protein (APP) and ubiquitin-B in Alzheimer's disease and Down's syndrome. Protein sequences encoded by the frame-shifted transcripts were shown to be present within nerve cells with neurofibrillary pathology. It is suggested that such frame-shifted proteins may play an important role in the pathogenesis of sporadic Alzheimer's disease.
38. Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 82:1991;239-259.
39. of special interest Braak H, Braak E. Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging. 18:1997;351-357 An update of what is the definitive study (see [38]) of the natural history of neurofibrillary lesions and Aβ deposits in the ageing human brain.
40. Sergeant N, David JP, Lefranc D, Vermersch P, Wattez A, Delacourte A. Different distribution of phosphorylated tau protein isoforms in Alzheimer's and Pick's diseases. FEBS Lett. 412:1997;578-582.
41. of special interest Delacourte A, Sergeant N, Wattez A, Gauvreau D, Robitaille Y. Vulnerable neuronal subsets in Alzheimer's and Pick's disease and distinguished by their tau isoform distribution and phosphorylation. Ann Neurol. 43:1998;193-204 This study shows that the filamentous tau pathology of Pick's disease is distinguished from that of Alzheimer's disease by the absence of four-repeat tau isoforms. It confirms the lack of phosphorylation of Pick bodies at Ser262 in tau (see [42]).
42. Probst A, Tolnay M, Langui D, Goedert M, Spillantini MG. Pick's disease: hyperphosphorylated tau protein segregates to the somatoaxonal compartment. Acta Neuropathol. 92:1996;588-596.
43. Spillantini MG, Bird TD, Ghetti B. Frontotemporal dementia and Parkinsonism linked to chromosome 17: a new group of tauopathies. Brain Pathol. 8:1998;387-402.
44. Spillantini MG, Crowther RA, Goedert M. Comparison of the neurofibrillary pathology in Alzheimer's disease and familial presenile dementia with tangles. Acta Neuropathol. 92:1996;42-48.
45. of special interest Spillantini MG, Goedert M, Crowther RA, Murrell JR, Farlow MR, Ghetti B. Familial multiple system tauopathy with presenile dementia: a disease with abundant neuronal and glial tau filaments. Proc Natl Acad Sci USA. 94:1997;4113-4118 This paper describes the neuropathological characteristics of a new familial disease belonging to the class of FTDP-17 dementias. Abundant filamentous tau deposits are found in nerve cells and glial cells in a number of brain regions. The filament morphologies differ from those of Alzheimer's disease: biochemically, they only contain tau isoforms with four microtubule-binding repeats.
46. of special interest Reed LA, Schmidt ML, Wszolek ZK, Balin BJ, Soontornnivqmkij V, Lee VMY, Trojanowski JQ, Schelper RL. The neuropathology of a chromosome 17-linked autosomal dominant parkinsonism and dementia (pallido-ponto-nigral degeneration). J Neuropathol Exp Neurol. 57:1998;588-601 This paper describes the neuropathology of pallido-ponto-nigral degeneration (PPND), a TFDP-17 dementia. Abundant filamentous tau deposits are found in the nerve cells and glial cells in a number of PPND brain regions. The filaments of PPND resemble those present in familial MSTD, as do the pathological tau bands.
47. Conrad C, Andreadis A, Trojanowski JQ, Dickson DW, Kang D, Chen X, Wiederholt W, Hansen L, Masliah E, Thal LJ, et al. Genetic evidence for the involvement of tau in progressive supranuclear palsy. Ann Neurol. 41:1997;277-281.
48. Higgins JJ, Litvan I, Pho LT, Li W, Nee LE. Progressive supranuclear gaze palsy is in linkage disequilibrium with the tau and not the α-synuclein gene. Neurology. 50:1998;270-273.
49. Wilhelmsen CC, Lynch T, Pavlou E, Higgins M, Nygaard TG. Localization of disinhibition-dementia-Parkinsonism-amyotrophy complex to 17q21-22. Am J Hum Genet. 55:1994;1159-1165.
50. of outstanding interest Poorkaj P, Bird TD, Wijsman E, Nemens E, Garruto RM, Anderson L, Andreadis A, Wiederholt WC, Raskind M, Schellenberg GD. Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol. 43:1998;815-825 The authors identified a valine to methionine mutation at residue 337 (Val337Met) of tau in Seattle family A and a proline to leucine mutation at residue 301 (Pro301Leu) in Seattle family D - two families with FTDP-17 dementias. Both changes are located in the microtubule-binding repeats of tau. The Val337Met substitution is found in all six tau isoforms, whereas the Pro301Leu change is found only in tau isoforms with four repeats. Tau filaments in Seattle family A contain all six tau isoforms in a hyperphosphorylated state and are indistinguishable from the tau filaments of Alzheimer's disease (see [44]).
51. of outstanding interest Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, Pickering-Brown S, Chakraverty S, Isaacs A, Grover A, et al. Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature. 393:1998;702-705 This paper describes three separate exonic and three separate intronic mutations in the tau gene in ten families with FTDP-17. The exonic mutations are a glycine to valine change at position 272, a proline to leucine change at position 301 (see [50]) and an arginine to tryptophan change at position 406. The intronic mutations are in the intron folowing exon 10, where they are located 13, 14 and 16 nucleotides from the splice-donor site. They disrupt a predicted stem-loop, which may result in increased splicing of exon 10. Exont rapping experiments were used to show that the intronic mutations do indeed lead to increased splicing of exon 10 of the tau gene.
52. of special interest Spillantini MG, Murrell JR, Goedert M, Farlow MR, Klug A, Ghetti B. Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. of outstanding interest Proc Natl Acad Sci USA. 95:1998;7737-7741 The authors identified an intronic mutation in the nucleotide adjacent to the splice-donor site of exon 10 of the tau gene in familial multiple system tauopathy with presenile dementia (MSTD), a FTDP-17 dementia. The mutation disrupts a predicted stem-loop, similar to the intronic mutations reported by Hutton et al. [51]. This disruption may result in increased splicing of exon 10, consistent with an increase in four-repeat tau isoforms in soluble tau extracted from brains of patients with familial MSTD. Tau filaments in familial MSTD contain only four-repeat tau isoforms (see [45]).
53. Götz J, Probst A, Spillantini MG, Schäfer T, Jakes R, Bürki K, Goedert M. Somatodendritic localisation and hyperphosphorylation of tau protein in transgenic mice expressing the longest human brain tau isoform. EMBO J. 14:1995;1304-1313.
54. Forno LS. Neuropathology of Parkinson's disease. J Neuropathol Exp Neurol. 55:1996;259-272.
55. Golbe LI, Di Iorio G, Bonavita V, Miller DC, Duvoisin RC. A large kindred with autosomal dominant Parkinson's disease. Ann Neurol. 27:1990;276-282.
56. Duvoisin RC. Familial Parkinson's disease. Neurosci News. 1:1998;43-46.
57. of outstanding interest Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, et al. Mutation in the α-synuclein gene identified in families with Parkinson's disease. Science. 276:1997;2045-2047 This report represents the first identified genetic, cause of Parkinson's disease. The authors identified an alanine to threonine mutation at residue 53 in α-synuclein in a large Italian - American family (Contursi kindred) and three small Greek pedigrees with early-onset Parkinson's disease.
58. of outstanding interest Krüger R, Kuhn W, Müller T, Woitalla D, Graeber M, Kösel S, Przuntek H, Epplen JT, Schöls L, Riess O. Ala30Pro mutation in the gene encoding α-synuclein in Parkinson's disease. of special interest Nat Genet. 18:1998;106-108 The authors identified an alanine to proline mutation at residue 30 in α-synuclein in a German pedigree with early-onset familial Parkinson's disease. This finding firmly establishes that missense mutations in the α-synuclein gene can lead to Parkinson's disease (see also [57]).
59. of outstanding interest Kitada K, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature. 392:1998;605-608 The authors report that deletion mutations in the parkin gene underlie a rare juvenile, autosomal-recessively inherited form of parkinsonism (AR-JP). Parkin is a 465 amino acid protein of unknown function that shows some sequence similarities with ubiquitin at its amino terminus. Unlike Parkinson's disease, AR-JP is not characterised by Lewy bodies and Lewy neurites.
60. Goedert M, Jakes R, Spillantini MG. Alpha-synuclein and the Lewy body. Neurosci News. 1:1998;47-52.
61. Weinreb PH, Zhen W, Poon AW, Conway KA, Lansbury PT. NACP, a protein implicated in Alzheimer's disease and learning, is natively unfolded. Biochemistry. 35:1996;13709-13715.
62. of special interest Davidson WS, Jonas A, Clayton DF, George JM. Stabilization of α-synuclein secondary structure upon binding to synthetic membranes. J Biol Chem. 273:1998;9443-9449 The authors demonstrate that α-synuclein binds to artificial vesicle rich in acidic phospholipids through its amino-terminal repeats. Lipid binding is accompanied by an increase in α-helicity from 3% to approximately 80%, consistent with the view that α-synuclein becomes structured upon binding.
63. of special interest Spillantini MG, Schmidt ML, Lee VM-Y, Trojanowski JQ, Jakes R, Goedert M. α-Synuclein in Lewy bodies. of outstanding interest Nature. 388:1997;839-840 This paper shows that Lewy bodies and Lewy neurites of idiopathic Parkinson's disease and dementia with Lewy bodies are strongly immunoreactive for α-synuclein. Together with [57,58], this finding suggests that Parkinson's disease and dementia with Lewy bodies are α-synucleinopathies.
64. Wakabayashi K, Matsumoto K, Takayama K, Yoshimoto M, Takahashi H. NACP, a presynaptic protein, immunoreactivity in Lewy bodies in Parkinson's disease. Neurosci Lett. 239:1997;45-48.
65. Takeda A, Mallory M, Sundsmo M, Honer W, Hansen L, Masliah E. Abrnoaml accumulation of NACP/α-synuclein in neurodegenerative disorders. Am J Pathol. 152:1998;367-372.
66. Irizarry MC, Growdon W, Gomez-Isla T, Newell K, George JM, Clayton DF, Hyman BT. Nigral and cortical Lewy bodies and dystrophic nigral neurites in Parkinson's disease and cortical Lewy body disease contain α-synuclein immunoreactivity. J Neuropathol Exp Neurol. 57:1998;334-337.
67. of special interest Baba M, Nakajo S, Tu PH, Tomita T, Nakaya K, Lee VM-Y, Trojanowski JQ, Iwatsubo T. Aggregation of α-snyclein in Lewi bodies of sporadic Parkinson's disease and dementia with Lewy bodies. Am J Pathol. 152:1998;879-884 This paper confirms the presence of α-synuclein in Lewy bodies and Lewy neurites. In addition, it shows that some filamentous and granular material in purified Lewy bodies is labelled with α-snyclein antibodies. In Western blots, purified Lewy bodies appear to contain mostly truncated α-synuclein.
68. of special interest Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M. α-Synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with Lewy bodies. Proc Natl Acad Sci USA. 95:1998;6469-6473 This paper demonstrates that full-length or close to full-length α-synuclein is present in Lewy bodies and Lewy neurites and the α-synuclein staining is more extensive that ubiquitin staining. Isolated filaments were decorated by α-synuclein antibodies, indicating that α-synuclein is the major component of Lewy bodies and Lewy neurites.
69. Ince PG, Perry EK, Morris CM. Dementia with Lewy bodies. A distinct non-Alzheimer dementia syndrome? Brain Pathol. 8:1998;299-324.
70. Papp MI, Lantos PL. The distribution of oligodendroglial inclusions in multiple system atrophy and its relevance to clinical symptomatology. Brain. 117:1994;235-243.
71. of special interest Wakabayashi K, Yoshimoto M, Tsuji S, Takahashi H. α-Synuclein immunoreactivity in glial cytoplasmic inclusions in multiple system atrophy. Neurosci Lett. 249:1998;180-182 See annotation [73].
72. of special interest Mezey E, Dehejia A, Harta G, Papp MI, Polymeropoulos MH, Brownstein MJ. Alpha synuclein in neurodegenerative disorders: Murder of accomplice? Nat Med. 4:1998;755-757 See annotation [73].
73. of special interest Spillantini MG, Crowther RA, Jakes R, Cairns NJ, Lantos PL, Goedert M. Filamentous α-synuclein inclusions link multiple system atrophy with Parkinson's disease and dementia with Lewy bodies. Neurosci Lett. 251:1998;205-208 These papers [71-73] show that the glial and neuronal inclusions of mutiple system atrophy (MSA) are strongly immunoreactive for α-synuclein. Using immunoelectron microscopy, Spillantini et al. [73] found that filaments extracted from MSA brain are strongly labelled by α-synuclein antibodies, indicating that MSA is a third α-synucleinopathy (the first two being Parkinson's disease and dementia with Lewy bodies). The staining characteristics of α-synuclein filaments from MSA brain are identical to those of Lewy body filaments (see [68]).
74. La Spada AR, Wilson EM, Lubahn DB, Harding AE, Fischbeck KH. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature. 353:1991;77-79.
75. Davies SW, Beardsall K, Turmaine M, DiFiglia M, Aronin N, Bates GP. Are neuronal intranuclear inclusions the common neuropathology of triplet-repeat disorders with polyglutamine-repeat expansions? Lancet. 351:1998;131-133.
76. Perutz MF, Johnson T, Suzuki M, Finch JT. Glutamine repeats as polar zippers: their possible role in inherited neurodegenerative diseases. Proc Natl Acad Sci USA. 91:1994;5355-5358.
77. A novel gene containing a trinucleotide repeat that is unstable on Huntington's disease chromosomes. Cell. 72:1993;971-983.
78. Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A, Hetherington C, Lawton M, Trottier Y, Lehrach H, Davies SW, Bates GP. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell. 87:1996;493-506.
79. 156 repeat expansions develop abundant neuronal intranuclear inclusions before developing a neurological phenotype. These inclusions are immunoreactive for exon 1 of huntingtin and for ubiquitin. This work uncovers the pathogenetic mechanism underlying all diseases with expanded glutamine repeats.
80. of outstanding interest Scherzinger E, Lurz R, Turmaine M, Mangiarini L, Hollenbach B, Hasenbank R, Bates GP, Davies SW, Lehrach H, Wanker EE. Huntingtin-encoded polyglutamine expansions form amyloid-like protein aggregates in vitro and in vivo. Cell. 90:1997;549-558 This paper shows that recombinant exon 1 of huntingtin carrying polyglutamine stretches in the pathological range assembles into sheet-like structures that resemble the intranuclear inclusions discovered by Davies et al. [79].
81. of special interest DiFiglia M, Sapp E, Chase KO, Davies SW, Bates GP, Vonsattel JP, Aronin N. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science. 277:1997;1990-1993 This paper reports the presence of neuronal intranuclear inclusions in brain tissue from Huntington's disease patients. They were found to be immunoreactive with an antibody directed against the amino terminus of huntingtin and with an anti-ubiquitin antibody. Dystrophic neurites with similar staining and ultrastructural characteristics were also observed. Immunoblot analysis suggests cleavage of huntingtin before it enters the nucleus.
82. Roizin L, Stellar S, Liu JC. Neuronal nuclear-cytoplasmic changes in Huntington's chorea: electron microscope investigations. Adv Neurol. 23:1979;95-122.
83. of outstanding interest Paulson HL, Perez MK, Trottier Y, Trojanowski JQ, Subramony SH, Das SS, Vig P, Mandel JL, Fischbeck KH, Pittman RN. Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3. Neuron. 19:1997;333-344 This paper describes the presence of neuronal intranuclear inclusions in spinocerebellar ataxia type-3. The first immunohistochemical demonstration of neuronal intranuclear inclusions in a human trinucleotide repeat disorder.
84. Skinner PJ, Koshy BT, Cummings CJ, Klement IA, Helin K, Servadio A, Zoghbi HY, Orr HT. Ataxin-1 with an expanded glutamine tract alters nuclear matrix-associated structures. Nature. 389:1997;971-974.
85. of special interest Cummings CJ, Mancini MA, Antalffy B, De Franco DB, Orr HT, Zoghbi HY. Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1. Nat Genet. 19:1998;148-154 This paper demonstrates the staining of neuronal intranuclear inclusions for the 20S proteasome and the molecular chaperone HDJ-2/HSDJ. Overexpression of antrophin-1 in HeLa cells leads to the formation of intranuclear inclusions immunoreactive for the 20S proteasome and HDJ-2/HSDJ. Overexpression of HDJ-2/HSDJ decreases the frequency of inclusions.
86. of special interest Ii K, Itoh H, Tanaka K, Hirano A. Immunocytochemical co-localization of the proteasome in ubiquitinated structures in neurodegenerative diseases and the elderly. J Neuropathol Exp Neurol. 56:1997;125-131 This paper shows that both ubiquitinated Lewy bodies of Parkinson's disease and dementia with Lewy bodies and ubiquitinated dystrophic neurites of Alzheimer's disease are immunoreactive for the 20S proteasome.
87. Igarashi S, Koide R, Shimohata Y, Yamada M, Hayashi Y, Takano H, Date H, Oyake M, Sato T, Sato A, et al. Suppression of aggregate formation and apoptosis by transglutaminase inhibitors in cells expressing truncated DRPLA protein with an expanded polyglutamine stretch. Nat Genet. 18:1998;111-117.
88. Becher MW, Kotzuk JA, Sharp AH, Davies SW, Bates GP, Price DL, Ross CA. Intranuclear neuronal inclusions in Huntington's disease and dentatorubral and pallidoluysian atrophy: correlation between the density of inclusions and IT15 CAG triplet repeat length. Neurobiol Dis. 4:1998;387-397.
89. Holmberg M, Duyckaerts C, Dürr A, Cancel G, Gourfinkel-An I, Damier P, Faucheux B, Trottier Y, Hirsch EC, Agid Y, Brice A. Spinocerebellar ataxia 7 (SCA7): a neurodegenerative disorder with neuronal intranuclear inclusions. Hum Mol Genet. 7:1998;913-918.
90. Li M, Miwa S, Kobayashi Y, Merry DE, Yamamoto M, Tanaka F, Doyu M, Hashizume Y, Fischbeck KH, Sobue G. Nuclear inclusions of the androgen receptor protein in spinal and bulbar muscular atrophy. Ann Neurol. 44:1998;249-254.
91. of special interest Ordway JM, Tallaksen-Greene S, Gutekunst CA, Bernstein EM, Cearley JA, Wiener HW, Dure LS, Lindsey R, Hersch SM, Jope R, et al. Ectopically expressed CAG repeats cause intranuclear inclusions and a progressive late onset neurological phenotype in the mouse. Cell. 91:1997;753-763 The authors generated transgenic mice that express hypoxanthine phosphoribosyltransferase with a long polyglutamine tract in nerve cells. These mice display a neurological phenotype and develop large numbers of neuronal intranuclear inclusions. This finding provides further compelling evidence that long polyglutamine tracts are inherently toxic to nerve cells.
92. of special interest Warrick JM, Paulson HL, Gray-Board GL, Bui QT, Fischbeck KH, Pittman RN, Bonini NM. Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in Drosphila. Cell.