Alexander Disease: A Genetic Disorder of Astrocytes

  • Michael Brenner
  • James E. Goldman
  • Roy A. Quinlan
  • Albee Messing


Glial Fibrillary Acidic Protein Intermediate Filament Glial Fibrillary Acidic Protein Expression Glial Fibrillary Acidic Protein Level Alexander Disease 



Central nervous system


Cerebrospinal fluid


Electron microscopy


γ-Amino butyric acid


Glutamic acid decarboxylase


Glial fibrillary acidic protein


Green fluorescent protein


Glial l-glutamate transporter


Human GFAP


c-Jun amino-terminal kinase


Mendelian inheritance in man


Magnetic resonance imaging


Sodium dodecyl sulfate polyacrylamide gel electrophoresis


Tumor necrosis factor α


Thyrotropin releasing hormone



We thank Daniel M. Bolt for statistical assistance, Marjo van der Knaap for permission to use Fig. 24.1, Anne B. Johnson for permission to use Fig. 24.2, and Rong Li for the images in Fig. 24.7. The authors would also like to thank the editors for giving them the opportunity to write this extensive, and final, review of their careers. One more would be too many. This work was supported by NINDS grant P01NS42803.


  1. Alexander WS (1949) Progressive fibrinoid degeneration of fibrillary astrocytes associated with mental retardation in a hydrocephalic infant. Brain 72:373–381.PubMedGoogle Scholar
  2. Andra K, Lassmann H, Bittner R, Shorny S, Fassler R, Propst F, Wiche G (1997) Targeted inactivation of plectin reveals essential function in maintaining the integrity of skin, muscle, and heart cytoarchitecture. Genes Dev 11:3143–3156.PubMedGoogle Scholar
  3. Aoki Y, Haginoya K, Munakata M, Yokoyama H, Nishio T, Togashi N, Ito T, Suzuki Y, Kure S, Iinuma K, Brenner M, Matsubara Y (2001) A novel mutation in glial fibrillary acidic protein gene in a patient with Alexander disease. Neurosci Lett 312:71–74.PubMedGoogle Scholar
  4. Asahina N, Okamoto T, Sudo A, Kanazawa N, Tsujino S, Saitoh S (2006) An infantile-juvenile form of Alexander disease caused by a R79H mutation in GFAP. Brain Dev 28:131–133.PubMedGoogle Scholar
  5. Bar H, Mucke N, Kostareva A, Sjoberg G, Aebi U, Herrmann H (2005) Severe muscle disease-causing desmin mutations interfere with in vitro filament assembly at distinct stages. Proc Natl Acad Sci USA 102:15099–15104.PubMedGoogle Scholar
  6. Bar H, Kostareva A, Sjoberg G, Sejersen T, Katus HA, Herrmann H (2006a) Forced expression of desmin and desmin mutants in cultured cells: impact of myopathic missense mutations in the central coiled-coil domain on network formation. Exp Cell Res 312:1554–1565.Google Scholar
  7. Bar H, Mucke N, Ringler P, Muller SA, Kreplak L, Katus HA, Aebi U, Herrmann H (2006b) Impact of disease mutations on the desmin filament assembly process. J Mol Biol 360:1031–1042.Google Scholar
  8. Bassuk AG, Joshi A, Burton BK, Larsen MB, Burrowes DM, Stack C (2003) Alexander disease with serial MRS and a new mutation in the glial fibrillary acidic protein gene. Neurology 61:1014–1015.PubMedGoogle Scholar
  9. Becker LE, Teixeira F (1988) Alexander’s disease. In: Norenberg MD, Hertz L, Schousboe A, eds), The biochemical pathology of astrocytes (Alan R. Liss. New York: pp 179–190.Google Scholar
  10. Bongcam-Rudloff E, Nister M, Betsholtz C, Wang JL, Stenman G, Huebner K, Croce CM, Westermark B (1991) Human glial fibrillary acidic protein: complementary DNA cloning, chromosome localization, and messenger RNA expression in human glioma cell lines of various phenotypes. Cancer Res 51:1553–1560.PubMedGoogle Scholar
  11. Boor PK, Groot K, de Waisfisz Q, Kamphorst W, Oudejans CB, Powers JM, Pronk JC, Scheper GC, Knaap MS van der (2005) MLC1: a novel protein in distal astroglial processes. J Neuropathol Exp Neurol 64:412–419.PubMedGoogle Scholar
  12. Borrett D, Becker LE (1985) Alexander’s disease. A disease of astrocytes. Brain 108 (Part 2):367–385.PubMedGoogle Scholar
  13. Brenner M (1994) Structure and transcriptional regulation of the GFAP gene. Brain Pathol 4:245–257.PubMedGoogle Scholar
  14. Brenner M, Lampel K, Nakatani Y, Mill J, Banner C, Mearow K, Dohadwala M, Lipsky R, Freese E (1990) Characterization of human cDNA and genomic clones for glial fibrillary acidic protein. Brain Res Mol Brain Res 7:277–286.PubMedGoogle Scholar
  15. Brenner M, Kisseberth WC, Su Y, Besnard F, Messing A (1994) GFAP promoter directs astrocyte-specific expression in transgenic mice. J Neurosci 14:1030–1037.PubMedGoogle Scholar
  16. Brenner M, Johnson AB, Boespflug-Tanguy O, Rodriguez D, Goldman JE, Messing A (2001) Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease. Nat Genet 27:117–120.PubMedGoogle Scholar
  17. Brockmann K, Meins M, Taubert A, Trappe R, Grond M, Hanefeld F (2003) A novel GFAP mutation and disseminated white matter lesions: adult alexander disease? Eur Neurol 50:100–105.PubMedGoogle Scholar
  18. Caceres-Marzal C, Vaquerizo J, Galan E, Fernandez S (2006) Early mitochondrial dysfunction in an infant with Alexander disease. Pediatr Neurol 35:293–296.PubMedGoogle Scholar
  19. Castellani RJ, Perry G, Harris PL, Monnier VM, Cohen ML, Smith MA (1997) Advanced glycation modification of Rosenthal fibers in patients with Alexander disease. Neurosci Lett 231:79–82.PubMedGoogle Scholar
  20. Castellani RJ, Perry G, Harris PL, Cohen ML, Sayre LM, Salomon RG, Smith MA (1998) Advanced lipid peroxidation end-products in Alexander’s disease. Brain Res 787:15–18.PubMedGoogle Scholar
  21. Chartier-Harlin MC, Kachergus J, Roumier C, Mouroux V, Douay X, Lincoln S, Levecque C, Larvor L, Andrieux J, Hulihan M, Waucquier N, Defebvre L, Amouyel P, Farrer M, Destee A (2004) Alpha-synuclein locus duplication as a cause of familial Parkinson’s disease. Lancet 364:1167–1169.PubMedGoogle Scholar
  22. Chen WJ, Liem RK (1994) The endless story of the glial fibrillary acidic protein. J Cell Sci 107:2299–2311.PubMedGoogle Scholar
  23. Cooper DN, Youssoufian H (1988) The CpG dinucleotide and human genetic disease. Hum Genet 78:151–155.PubMedGoogle Scholar
  24. Cotton RG, Scriver CR (1998) Proof of “disease causing” mutation. Hum Mutat 12:1–3.PubMedGoogle Scholar
  25. Crome L (1953) Megalencephaly associated with hyaline pan-neuropathy. Brain 76:215–228.PubMedGoogle Scholar
  26. Perng M, Der Su M, Wen SF, Li R, Gibbon T, Prescott AR, Brenner M, Quinlan RA (2006) The Alexander disease-causing glial fibrillary acidic protein mutant, R416W, accumulates into Rosenthal fibers by a pathway that involves filament aggregation and the association of alpha B-crystallin and HSP27. Am J Hum Genet 79:197–213.Google Scholar
  27. Dinopoulos A, Gorospe JR, Egelhoff JC, Cecil KM, Nicolaidou P, Morehart P, DeGrauw T (2006) Discrepancy between neuroimaging findings and clinical phenotype in Alexander disease. AJNR Am J Neuroradiol 27:2088–2092.PubMedGoogle Scholar
  28. Duckett S, Schwartzman RJ, Osterholm J, Rorke LB, Friedman D, McLellan TL (1992) Biopsy diagnosis of familial Alexander’s disease. Pediatr Neurosurg 18:134–138.PubMedGoogle Scholar
  29. Ellisdon AM, Pearce MC, Bottomley SP (2007) Mechanisms of ataxin-3 misfolding and fibril formation: kinetic analysis of a disease-associated polyglutamine protein. J Mol Biol 368:595–605.PubMedGoogle Scholar
  30. Eng LF, Ghirnikar RS (1994) GFAP and astrogliosis. Brain Pathol 4:229–237.PubMedGoogle Scholar
  31. Eng LF, Lee YL, Kwan H, Brenner M, Messing A (1998) Astrocytes cultured from transgenic mice carrying the added human glial fibrillary acidic protein gene contain Rosenthal fibers. J Neurosci Res 53:353–360.PubMedGoogle Scholar
  32. Escourolle R, Baecque C, de Gray F, Baumann N, Hauw JJ (1979) [Electron microscopic and neurochemical study of Alexander’s disease (author’s transl)]. Acta Neuropathol 45:133–140.PubMedGoogle Scholar
  33. Farrell K, Chuang S, Becker LE (1984) Computed tomography in Alexander’s disease. Ann Neurol 15:605–607.PubMedGoogle Scholar
  34. Friede RL (1964) Alexander’s disease. Arch Neurol 11:414–422.PubMedGoogle Scholar
  35. Friedman JH, Ambler M (1992) Progressive parkinsonism associated with Rosenthal fibers: senile-onset Alexander’s disease? Neurology 42:1733–1735.PubMedGoogle Scholar
  36. Fuchs E (1996) The cytoskeleton and disease: genetic disorders of intermediate filaments. Annu Rev Genet 30:197–231.PubMedGoogle Scholar
  37. Fuchs E, Cleveland DW (1998) A structural scaffolding of intermediate filaments in health and disease. Science 279:514–519.PubMedGoogle Scholar
  38. Gessaga EC, Anzil AP (1975) Rod-shaped filamentous inclusions and other ultrastructural features in a cerebellar astrocytoma. Acta Neuropathol (Berl) 33:119–127.Google Scholar
  39. Giasson BI, Uryu K, Trojanowski JQ, Lee VM (1999) Mutant and wild type human alpha-synucleins assemble into elongated filaments with distinct morphologies in vitro. J Biol Chem 274:7619–7622.PubMedGoogle Scholar
  40. Gingold MK, Bodensteiner JB, Schochet SS, Jaynes M (1999) Alexander’s disease: unique presentation. J Child Neurol 14:325–329.PubMedGoogle Scholar
  41. Goebel HH (2003) Congenital myopathies at their molecular dawning. Muscle Nerve 27:527–548.PubMedGoogle Scholar
  42. Goldman JE, Corbin E (1988) Isolation of a major protein component of Rosenthal fibers. Am J Pathol 130:569–578.PubMedGoogle Scholar
  43. Goldman JE, Corbin E (1991) Rosenthal fibers contain ubiquitinated alpha B-crystallin. Am J Pathol 139:933–938.PubMedGoogle Scholar
  44. Gomi H, Yokoyama T, Fujimoto K, Ikeda T, Katoh A, Itoh T, Itohara S (1995) Mice devoid of the glial fibrillary acidic protein develop normally and are susceptible to scrapie prions. Neuron 14:29–41.PubMedGoogle Scholar
  45. Gordon N (2003) Alexander disease. Eur J Paediatr Neurol 7:395–399.PubMedGoogle Scholar
  46. Gorospe JR, Maletkovic J (2006) Alexander disease and megalencephalic leukoencephalopathy with subcortical cysts: leukodystrophies arising from astrocyte dysfunction. Ment Retard Dev Disabil Res Rev 12:113–122.PubMedGoogle Scholar
  47. Gorospe JR, Naidu S, Johnson AB, Puri V, Raymond GV, Jenkins SD, Pedersen RC, Lewis D, Knowles P, Fernandez R, Vivo D, De Knaap MS, van der Messing A, Brenner M, Hoffman EP (2002) Molecular findings in symptomatic and pre-symptomatic Alexander disease patients. Neurology 58:1494–1500.PubMedGoogle Scholar
  48. Hagemann TL, Gaeta SA, Smith MA, Johnson DA, Johnson JA, Messing A (2005) Gene expression analysis in mice with elevated glial fibrillary acidic protein and Rosenthal fibers reveals a stress response followed by glial activation and neuronal dysfunction. Hum Mol Genet 14:2443–2458.PubMedGoogle Scholar
  49. Hagemann TL, Connor JX, Messing A (2006) Alexander disease-associated glial fibrillary acidic protein mutations in mice induce Rosenthal fiber formation and a white matter stress response. J Neurosci 26:11162–11173.PubMedGoogle Scholar
  50. Hedberg KK, Chen LB (1986) Absence of intermediate filaments in a human adrenal cortex carcinoma-derived cell line. Exp Cell Res 163:509–517.PubMedGoogle Scholar
  51. Herndon RM, Rubinstein LJ, Freeman JM, Mathieson G (1970) Light and electron microscopic observations on Rosenthal fibers in Alexander’s disease and in multiple sclerosis. J Neuropathol Exp Neurol 29:524–551.PubMedGoogle Scholar
  52. Herrmann H, Strelkov SV, Feja B, Rogers KR, Brettel M, Lustig A, Haner M, Parry DA, Steinert PM, Burkhard P, Aebi U (2000) The intermediate filament protein consensus motif of helix 2B: its atomic structure and contribution to assembly. J Mol Biol 298:817–832.PubMedGoogle Scholar
  53. Hsiao VC, Tian R, Long H, Perng M, Der Brenner M, Quinlan RA, Goldman JE (2005) Alexander-disease mutation of GFAP causes filament disorganization and decreased solubility of GFAP. J Cell Sci 118:2057–2065.PubMedGoogle Scholar
  54. Hurst LD, Ellegren H (1998) Sex biases in the mutation rate. Trends Genet 14:446–452.PubMedGoogle Scholar
  55. Imamura A, Orii KE, Mizuno S, Hoshi H, Kondo T (2002) MR imaging and 1H-MR spectroscopy in a case of juvenile Alexander disease. Brain Dev 24:723–726.PubMedGoogle Scholar
  56. Inagaki N, Hayashi T, Arimura T, Koga Y, Takahashi M, Shibata H, Teraoka K, Chikamori T, Yamashina A, Kimura A (2006) Alpha B-crystallin mutation in dilated cardiomyopathy. Biochem Biophys Res Commun 342:379–386.PubMedGoogle Scholar
  57. Isaacs A, Baker M, Vrieze F, Wavrant-De Hutton M (1998) Determination of the gene structure of human GFAP and absence of coding region mutations associated with frontotemporal dementia with parkinsonism linked to chromosome 17. Genomics 51:152–154.PubMedGoogle Scholar
  58. Ishigaki K, Ito Y, Sawaishi Y, Kodaira K, Funatsuka M, Hattori N, Nakano K, Saito K, Osawa M (2006) TRH therapy in a patient with juvenile Alexander disease. Brain Dev 28:663–667.PubMedGoogle Scholar
  59. Iwaki T, Kume-Iwaki A, Liem RK, Goldman JE (1989) Alpha B-crystallin is expressed in non-lenticular tissues and accumulates in Alexander’s disease brain. Cell 57:71–78.PubMedGoogle Scholar
  60. Iwaki T, Wisniewski T, Iwaki A, Corbin E, Tomokane N, Tateishi J, Goldman JE (1992) Accumulation of alpha B-crystallin in central nervous system glia and neurons in pathologic conditions. Am J Pathol 140:345–356.PubMedGoogle Scholar
  61. Iwaki T, Iwaki A, Tateishi J, Sakaki Y, Goldman JE (1993) Alpha B-crystallin and 27-kd heat shock protein are regulated by stress conditions in the central nervous system and accumulate in Rosenthal fibers. Am J Pathol 143:487–495.PubMedGoogle Scholar
  62. Jacob J, Robertson NJ, Hilton DA (2003) The clinicopathological spectrum of Rosenthal fibre encephalopathy and Alexander’s disease: a case report and review of the literature. J Neurol Neurosurg Psychiatry 74:807–810.PubMedGoogle Scholar
  63. Johnson AB (1996) Alexander disease. In: Handbook of clinical neurology, Elsevier Science B.V. Amsterdam: pp 701–710. Google Scholar
  64. Johnson AB, Bettica A (1989) On-grid immunogold labeling of glial intermediate filaments in epoxy-embedded tissue. Am J Anat 185:335–341.PubMedGoogle Scholar
  65. Johnson AB, Brenner M (2003) Alexander’s disease: clinical, pathologic, and genetic features. J Child Neurol 18:625–632.PubMedGoogle Scholar
  66. Johnston MV (2005) Excitotoxicity in perinatal brain injury. Brain Pathol 15:234–240.PubMedGoogle Scholar
  67. Kawai M, Sakai N, Miyake S, Tsukamoto H, Akagi M, Inui K, Mushiake S, Taniike M, Ozono K (2006) Novel mutation of gene coding for glial fibrillary acidic protein in a Japanese patient with Alexander disease. Brain Dev 28:60–62.PubMedGoogle Scholar
  68. Kinoshita T, Imaizumi T, Miura Y, Fujimoto H, Ayabe M, Shoji H, Okamoto Y, Takashima H, Osame M, Nakagawa M (2003) A case of adult-onset Alexander disease with Arg416Trp human glial fibrillary acidic protein gene mutation. Neurosci Lett 350:169–172.PubMedGoogle Scholar
  69. Klein EA, Anzil AP (1994) Prominent white matter cavitation in an infant with Alexander’s disease. Clin Neuropathol 13:31–38.PubMedGoogle Scholar
  70. Koyama S, Arawaka S, Chang-Hong R, Wada M, Kawanami T, Kurita K, Kato M, Nagai M, Aoki M, Itoyama Y, Sobue G, Chan PH, Kato T (2006) Alteration of familial ALS-linked mutant SOD1 solubility with disease progression: its modulation by the proteasome and Hsp70. Biochem Biophys Res Commun 343:719–730.PubMedGoogle Scholar
  71. Koyama Y, Goldman JE (1999) Formation of GFAP cytoplasmic inclusions in astrocytes and their disaggregation by alphaB-crystallin. Am J Pathol 154:1563–1572.PubMedGoogle Scholar
  72. Kress Y, Gaskin F, Horoupian DS, Brosnan C (1981) Nickel induction of Rosenthal fibers in rat brain. Brain Res 210:419–425.PubMedGoogle Scholar
  73. Kwong JQ, Beal MF, Manfredi G (2006) The role of mitochondria in inherited neurodegenerative diseases. J Neurochem 97:1659–1675.PubMedGoogle Scholar
  74. Kyllerman M, Rosengren L, Wiklund LM, Holmberg E (2005) Increased levels of GFAP in the cerebrospinal fluid in three subtypes of genetically confirmed Alexander disease. Neuropediatrics 36:319–323.PubMedGoogle Scholar
  75. Ledeen RW, Chakraborty G (1998) Cytokines, signal transduction, and inflammatory demyelination: review and hypothesis. Neurochem Res 23:277–289.PubMedGoogle Scholar
  76. Lee JM, Kim AS, Lee SJ, Cho SM, Lee DS, Choi SM, Kim DK, Ki CS, Kim JW (2006) A case of infantile Alexander disease accompanied by infantile spasms diagnosed by DNA analysis. J Korean Med Sci 21:954–957.PubMedGoogle Scholar
  77. Leegwater PA, Yuan BQ, Steen J, van der Mulders J, Konst AA, Boor PK, Mejaski-Bosnjak V, Maarel SM, van der Frants RR, Oudejans CB, Schutgens RB, Pronk JC, Knaap MS van der (2001) Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts. Am J Hum Genet 68:831–838.PubMedGoogle Scholar
  78. Li R, Messing A, Goldman J, Brenner M (2002a) GFAP mutations in Alexander disease. Int J Dev Neurosci 20:259.Google Scholar
  79. Li R, Johnson AB, Salomons GS, van der Knaap MS, Rodriguez D, Boespflug-Tanguy O, Gorospe JR, Goldman JE, Messing A, Brenner M (2005a) Propensity for paternal inheritance of de novo mutations in Alexander disease. Hum Genet 1–8. Google Scholar
  80. Li R, Johnson AB, Salomons G, Goldman JE, Naidu S, Quinlan R, Cree B, Ruyle SZ, Banwell B, Siebert MDH Jr, Rolf CM, Cox H, Reddy A, Gutierrez-Solana LG, Collins A, Weller RO, Messing A, Knaap MS, van der Brenner M (2005b) Glial fibrillary acidic protein mutations in infantile, juvenile, and adult forms of Alexander disease. Ann Neurol 57:310–326.Google Scholar
  81. Li WH, Yi S, Makova K (2002b) Male-driven evolution. Curr Opin Genet Dev 12:650–656.Google Scholar
  82. Lowe J, Blanchard A, Morrell K, Lennox G, Reynolds L, Billett M, Landon M, Mayer RJ (1988) Ubiquitin is a common factor in intermediate filament inclusion bodies of diverse type in man, including those of Parkinson’s disease, Pick’s disease, and Alzheimer’s disease, as well as Rosenthal fibres in cerebellar astrocytomas, cytoplasmic bodies in muscle, and mallory bodies in alcoholic liver disease. J Pathol 155:9–15.PubMedGoogle Scholar
  83. Lowe J, McDermott H, Pike I, Spendlove I, Landon M, Mayer RJ (1992) Alpha B crystallin expression in non-lenticular tissues and selective presence in ubiquitinated inclusion bodies in human disease. J Pathol 166:61–68.PubMedGoogle Scholar
  84. Ma L, Yamada S, Wirtz D, Coulombe PA (2001) A ‘hot-spot’ mutation alters the mechanical properties of keratin filament networks. Nat Cell Biol 3:503–506.PubMedGoogle Scholar
  85. Matute C, Alberdi E, Ibarretxe G, Sanchez-Gomez MV (2002) Excitotoxicity in glial cells. Eur J Pharmacol 447:239–246.PubMedGoogle Scholar
  86. McCall MA, Gregg RG, Behringer RR, Brenner M, Delaney CL, Galbreath EJ, Zhang CL, Pearce RA, Chiu SY, Messing A (1996) Targeted deletion in astrocyte intermediate filament (Gfap) alters neuronal physiology. Proc Natl Acad Sci USA 93:6361–6366.PubMedGoogle Scholar
  87. Meins M, Brockmann K, Yadav S, Haupt M, Sperner J, Stephani U, Hanefeld F (2002) Infantile Alexander disease: a GFAP mutation in monozygotic twins and novel mutations in two other patients. Neuropediatrics 33:194–198.PubMedGoogle Scholar
  88. Messing A, Brenner M (2003) Alexander disease: GFAP mutations unify young and old. Lancet Neurol 2:75PubMedGoogle Scholar
  89. Messing A, Goldman JE (2004) Alexander disease. In: Lazzarini RA, ed), Myelin and its diseases (Elsevier Academic Press. San Diego: pp 851–866.Google Scholar
  90. Messing A, Head MW, Galles K, Galbreath EJ, Goldman JE, Brenner M (1998) Fatal encephalopathy with astrocyte inclusions in GFAP transgenic mice. Am J Pathol 152:391–398.PubMedGoogle Scholar
  91. Messing A, Goldman JE, Johnson AB, Brenner M (2001) Alexander disease: new insights from genetics. J Neuropathol Exp Neurol 60:563–573.PubMedGoogle Scholar
  92. Nachman MW, Crowell SL (2000) Estimate of the mutation rate per nucleotide in humans. Genetics 156:297–304.PubMedGoogle Scholar
  93. Namekawa M, Takiyama Y, Aoki Y, Takayashiki N, Sakoe K, Shimazaki H, Taguchi T, Tanaka Y, Nishizawa M, Saito K, Matsubara Y, Nakano I (2002) Identification of GFAP gene mutation in hereditary adult-onset Alexander’s disease. Ann Neurol 52:779–785.PubMedGoogle Scholar
  94. Nicholl ID, Quinlan RA (1994) Chaperone activity of alpha-crystallins modulates intermediate filament assembly. EMBO J 13:945–953.PubMedGoogle Scholar
  95. Nobuhara Y, Nakahara K, Higuchi I, Yoshida T, Fushiki S, Osame M, Arimura K, Nakagawa M (2004) Juvenile form of Alexander disease with GFAP mutation and mitochondrial abnormality. Neurology 63:1302–1304.PubMedGoogle Scholar
  96. Ogasawara N (1965) [Multiple sclerosis with Rosenthal’s fibers]. Acta Neuropathol 5:61–68.PubMedGoogle Scholar
  97. Okamoto Y, Mitsuyama H, Jonosono M, Hirata K, Arimura K, Osame M, Nakagawa M (2002) Autosomal dominant palatal myoclonus and spinal cord atrophy. J Neurol Sci 195:71–76.PubMedGoogle Scholar
  98. Pappolla MA (1986) Lewy bodies of Parkinson’s disease. Immune electron microscopic demonstration of neurofilament antigens in constituent filaments . Arch Pathol Lab Med 110:1160–1163.PubMedGoogle Scholar
  99. Parry DA, Steinert PM (1999) Intermediate filaments: molecular architecture, assembly, dynamics and polymorphism. Q Rev Biophys 32:99–187.PubMedGoogle Scholar
  100. Pekny M, Leveen P, Pekna M, Eliasson C, Berthold CH, Westermark B, Betsholtz C (1995) Mice lacking glial fibrillary acidic protein display astrocytes devoid of intermediate filaments but develop and reproduce normally. EMBO J 14:1590–1598.PubMedGoogle Scholar
  101. Perng MD, Cairns L, den IP, van Prescott A, Hutcheson AM, Quinlan RA (1999a) Intermediate filament interactions can be altered by HSP27 and alphaB-crystallin. J Cell Sci 112 (Part 13):2099–2112.Google Scholar
  102. Perng MD, Muchowski PJ, Den IP, van Wu GJ, Hutcheson AM, Clark JI, Quinlan RA (1999b) The cardiomyopathy and lens cataract mutation in alphaB-crystallin alters its protein structure, chaperone activity, and interaction with intermediate filaments in vitro. J Biol Chem 274:33235–33243.Google Scholar
  103. Perng MD, Wen SF, den IP, van Prescott AR, Quinlan RA (2004) Desmin aggregate formation by R120G alphaB-crystallin is caused by altered filament interactions and is dependent upon network status in cells. Mol Biol Cell 15:2335–2346.PubMedGoogle Scholar
  104. Pridmore CL, Baraitser M, Harding B, Boyd SG, Kendall B, Brett EM (1993) Alexander’s disease: clues to diagnosis. J Child Neurol 8:134–144.PubMedGoogle Scholar
  105. Probst EN, Hagel C, Weisz V, Nagel S, Wittkugel O, Zeumer H, Kohlschutter A (2003) Atypical focal MRI lesions in a case of juvenile Alexander’s disease. Ann Neurol 53:118–120.PubMedGoogle Scholar
  106. Quinlan R (2001) Cytoskeletal catastrophe causes brain degeneration. Nat Genet 27:10–11.PubMedGoogle Scholar
  107. Quinlan R (2002) Cytoskeletal competence requires protein chaperones. Prog Mol Subcell Biol 28:219–233.PubMedGoogle Scholar
  108. Quinlan RA, Hatzfeld M, Franke WW, Lustig A, Schulthess T, Engel J (1986) Characterization of dimer subunits of intermediate filament proteins. J Mol Biol 192:337–349.PubMedGoogle Scholar
  109. Quinlan RA, Brenner M, Goldman JE, Messing A (2007) GFAP and its role in Alexander disease. Exp Cell Res 313:2077–2087.PubMedGoogle Scholar
  110. Ralton JE, Lu X, Hutcheson AM, Quinlan RA (1994) Identification of two N-terminal non-alpha-helical domain motifs important in the assembly of glial fibrillary acidic protein. J Cell Sci 107:1935–1948.PubMedGoogle Scholar
  111. Reichard EA, Ball WS Jr, Bove KE (1996) Alexander disease: a case report and review of the literature. Pediatr Pathol Lab Med 16:327–343.PubMedGoogle Scholar
  112. Reynolds LP, Allen GV (2003) A review of heat shock protein induction following cerebellar injury. Cerebellum 2:171–177.PubMedGoogle Scholar
  113. Rodriguez D, Gauthier F, Bertini E, Bugiani M, Brenner M, Ng S, Goizet C, Gelot A, Surtees R, Pedespan JM, Hernandorena X, Troncoso M, Uziel G, Messing A, Ponsot G, Pham-Dinh D, Dautigny A, Boespflug-Tanguy O (2001) Infantile Alexander disease: spectrum of GFAP mutations and genotype-phenotype correlation. Am J Hum Genet 69:1134–1140.PubMedGoogle Scholar
  114. Rosenthal W (1898) Über eine eigenthümliche, mit syringomyelie complicirte geschwulst des rückenmarks. Bietr Pathol Anat 23:111–143.Google Scholar
  115. Russo LS Jr, Aron A, Anderson PJ (1976) Alexander’s disease: a report and reappraisal. Neurology 26:607–614.PubMedGoogle Scholar
  116. Salvi F, Aoki Y, Della Nave R, Vella A, Pastorelli F, Scaglione C, Matsubara Y, Mascalchi M (2005) Adult Alexander’s disease without leukoencephalopathy. Ann Neurol 58:813–814.PubMedGoogle Scholar
  117. Sawaishi Y, Hatazawa J, Ochi N, Hirono H, Yano T, Watanabe Y, Okudera T, Takada G (1999) Positron emission tomography in juvenile Alexander disease. J Neurol Sci 165:116–120.PubMedGoogle Scholar
  118. Sawaishi Y, Yano T, Takaku I, Takada G (2002) Juvenile Alexander disease with a novel mutation in glial fibrillary acidic protein gene. Neurology 58:1541–1543.PubMedGoogle Scholar
  119. Schmitt A, Gofferje V, Weber M, Meyer J, Mossner R, Lesch KP (2003) The brain-specific protein MLC1 implicated in megalencephalic leukoencephalopathy with subcortical cysts is expressed in glial cells in the murine brain. Glia 44:283–295.PubMedGoogle Scholar
  120. Schroder R, Kunz WS, Rouan F, Pfendner E, Tolksdorf K, Kappes-Horn K, Altenschmidt-Mehring M, Knoblich R, Ven PF, van der Reimann J, Furst DO, Blumcke I, Vielhaber S, Zillikens D, Eming S, Klockgether T, Uitto J, Wiche G, Rolfs A (2002) Disorganization of the desmin cytoskeleton and mitochondrial dysfunction in plectin-related epidermolysis bullosa simplex with muscular dystrophy. J Neuropathol Exp Neurol 61:520–530.PubMedGoogle Scholar
  121. Schuelke M, Smeitink J, Mariman E, Loeffen J, Plecko B, Trijbels F, Stockler-Ipsiroglu S, Heuvel L van den (1999) Mutant NDUFV1 subunit of mitochondrial complex I causes leukodystrophy and myoclonic epilepsy. Nat Genet 21:260–261.PubMedGoogle Scholar
  122. Schwankhaus JD, Parisi JE, Gulledge WR, Chin L, Currier RD (1995) Hereditary adult-onset Alexander’s disease with palatal myoclonus, spastic paraparesis, and cerebellar ataxia. Neurology 45:2266–2271.PubMedGoogle Scholar
  123. Seil FJ, Schochet SS Jr, Earle KM (1968) Alexander’s disease in an adult. Report of a case. Arch Neurol 19:494–502.PubMedGoogle Scholar
  124. Selcen D, Engel AG (2003) Myofibrillar myopathy caused by novel dominant negative alpha B-crystallin mutations. Ann Neurol 54:804–810.PubMedGoogle Scholar
  125. Shibuki K, Gomi H, Chen L, Bao S, Kim JJ, Wakatsuki H, Fujisaki T, Fujimoto K, Katoh A, Ikeda T, Chen C, Thompson RF, Itohara S (1996) Deficient cerebellar long-term depression, impaired eyeblink conditioning, and normal motor coordination in GFAP mutant mice. Neuron 16:587–599.PubMedGoogle Scholar
  126. Shiihara T, Kato M, Honma T, Ohtaki S, Sawaishi Y, Hayasaka K (2002) Fluctuation of computed tomographic findings in white matter in Alexander’s disease. J Child Neurol 17:227–230.PubMedGoogle Scholar
  127. Shiihara T, Sawaishi Y, Adachi M, Kato M, Hayasaka K (2004) Asymptomatic hereditary Alexander’s disease caused by a novel mutation in GFAP. J Neurol Sci 225:125–127.PubMedGoogle Scholar
  128. Shiroma N, Kanazawa N, Izumi M, Sugai K, Fukumizu M, Sasaki M, Hanaoka S, Kaga M, Tsujino S (2001) Diagnosis of Alexander disease in a Japanese patient by molecular genetic analysis. J Hum Genet 46:579–582.PubMedGoogle Scholar
  129. Shiroma N, Kanazawa N, Kato Z, Shimozawa N, Imamura A, Ito M, Ohtani K, Oka A, Wakabayashi K, Iai M, Sugai K, Sasaki M, Kaga M, Ohta T, Tsujino S (2003) Molecular genetic study in Japanese patients with Alexander disease: a novel mutation, R79L. Brain Dev 25:116–121.PubMedGoogle Scholar
  130. Singh R, Nielsen AL, Johansen MG, Jorgensen AL (2003) Genetic polymorphism and sequence evolution of an alternatively spliced exon of the glial fibrillary acidic protein gene, GFAP. Genomics 82:185–193.PubMedGoogle Scholar
  131. Sistermans EA, Coo RF, de Wijs IJ, de Oost BA Van (1998) Duplication of the proteolipid protein gene is the major cause of Pelizaeus-Merzbacher disease. Neurology 50:1749–1754.PubMedGoogle Scholar
  132. Smith FJ, Eady RA, Leigh IM, McMillan JR, Rugg EL, Kelsell DP, Bryant SP, Spurr NK, Geddes JF, Kirtschig G, Milana G, Bono AG, de Owaribe K, Wiche G, Pulkkinen L, Uitto J, McLean WH, Lane EB (1996a) Plectin deficiency results in muscular dystrophy with epidermolysis bullosa. Nat Genet 13:450–457.Google Scholar
  133. Smith MA, Siedlak SL, Richey PL, Nagaraj RH, Elhammer A, Perry G (1996b) Quantitative solubilization and analysis of insoluble paired helical filaments from Alzheimer disease. Brain Res 717:99–108.Google Scholar
  134. Smith TW, Tyler HR, Schoene WC (1975) Atypical astrocytes and Rosenthal fibers in a case of amyotrophic lateral sclerosis associated with a cerebral glioblastoma multiforme. Acta Neuropathol 31:29–34.PubMedGoogle Scholar
  135. Soellner P, Quinlan RA, Franke WW (1985) Identification of a distinct soluble subunit of an intermediate filament protein: tetrameric vimentin from living cells. Proc Natl Acad Sci USA 82:7929–7933.PubMedGoogle Scholar
  136. Spalke G, Mennel HD (1982) Alexander’s disease in an adult: clinicopathologic study of a case and review of the literature. Clin Neuropathol 1:106–112.PubMedGoogle Scholar
  137. Sreedharan J, Shaw CE, Jarosz J, Samuel M (2007) Alexander disease with hypothermia, microcoria, and psychiatric and endocrine disturbances. Neurology 68:1322–1323.PubMedGoogle Scholar
  138. Steinert PM, Marekov LN, Parry DA (1999) Molecular parameters of type IV alpha-internexin and type IV-type III alpha-internexin-vimentin copolymer intermediate filaments. J Biol Chem 274:1657–1666.PubMedGoogle Scholar
  139. Stumpf E, Masson H, Duquette A, Berthelet F, McNabb J, Lortie A, Lesage J, Montplaisir J, Brais B, Cossette P (2003) Adult Alexander disease with autosomal dominant transmission: a distinct entity caused by mutation in the glial fibrillary acid protein gene. Arch Neurol 60:1307–1312.PubMedGoogle Scholar
  140. Suzuki Y, Kanazawa N, Takenaka J, Okumura A, Negoro T, Tsujino S (2004) A case of infantile Alexander disease with a milder phenotype and a novel GFAP mutation, L90P. Brain Dev 26:206–208.PubMedGoogle Scholar
  141. Takanashi J, Sugita K, Tanabe Y, Niimi H (1998) Adolescent case of Alexander disease: MR imaging and MR spectroscopy. Pediatr Neurol 18:67–70.PubMedGoogle Scholar
  142. Takemura M, Gomi H, Colucci-Guyon E, Itohara S (2002) Protective role of phosphorylation in turnover of glial fibrillary acidic protein in mice. J Neurosci 22:6972–6979.PubMedGoogle Scholar
  143. Tanaka K, Watase K, Manabe T, Yamada K, Watanabe M, Takahashi K, Iwama H, Nishikawa T, Ichihara N, Kikuchi T, Okuyama S, Kawashima N, Hori S, Takimoto M, Wada K (1997) Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. Science 276:1699–1702.PubMedGoogle Scholar
  144. Tanaka KF, Takebayashi H, Yamazaki Y, Ono K, Naruse M, Iwasato T, Itohara S, Kato H, Ikenaka K (2007) Murine model of Alexander disease: analysis of GFAP aggregate formation and its pathological significance. Glia 55:617–631.PubMedGoogle Scholar
  145. Tang G, Xu Z, Goldman JE (2006) Synergistic effects of the SAPK/JNK and the proteasome pathway on glial fibrillary acidic protein (GFAP) accumulation in Alexander disease. J Biol Chem 281:38634–38643.PubMedGoogle Scholar
  146. Thyagarajan D, Chataway T, Li R, Gai WP, Brenner M (2004) Dominantly-inherited adult-onset leukodystrophy with palatal tremor caused by a mutation in the glial fibrillary acidic protein gene. Mov Disord 19:1244–1248.PubMedGoogle Scholar
  147. Tian R, Gregor M, Wiche G, Goldman JE (2006) Plectin regulates the organization of glial fibrillary acidic protein in Alexander disease. Am J Pathol 168:888–897.PubMedGoogle Scholar
  148. Toivola DM, Tao GZ, Habtezion A, Liao J, Omary MB (2005) Cellular integrity plus: organelle-related and protein-targeting functions of intermediate filaments. Trends Cell Biol 15:608–617.PubMedGoogle Scholar
  149. Towfighi J, Young R, Sassani J, Ramer J, Horoupian DS (1983) Alexander’s disease: further light-, and electron-microscopic observations. Acta Neuropathol 61:36–42.PubMedGoogle Scholar
  150. Townsend JJ, Wilson JF, Harris T, Coulter D, Fife R (1985) Alexander’s disease. Acta Neuropathol 67:163–166.PubMedGoogle Scholar
  151. Trollmann R, Kraus C, Orlova N, Rupprecht T, Wenzel D, Rauch A (2003) Diagnosesicherung des morbus Alexander in vivo durch mutationsanalyse des GFAP-gens. Monatsschr Kinderheilkd 3:311–314.Google Scholar
  152. Knaap MS, van der Naidu S, Breiter SN, Blaser S, Stroink H, Springer S, Begeer JC, Coster R, Van Barth PG, Thomas NH, Valk J, Powers JM (2001) Alexander disease: diagnosis with mr imaging. Am J Neuroradiol 22:541–552.PubMedGoogle Scholar
  153. Knaap MS, van der Salomons GS, Li R, Franzoni E, Gutierrez-Solana LG, Smit LM, Robinson R, Ferrie CD, Cree B, Reddy A, Thomas N, Banwell B, Barkhof F, Jakobs C, Johnson A, Messing A, Brenner M (2005) Unusual variants of Alexander’s disease. Ann Neurol 57:327–338.PubMedGoogle Scholar
  154. Knaap MS, van der Ramesh V, Schiffmann R, Blaser S, Kyllerman M, Gholkar A, Ellison DW, Voorn JP, van der Dooren SJ, van Jakobs C, Barkhof F, Salomons GS (2006) Alexander disease: ventricular garlands and abnormalities of the medulla and spinal cord. Neurology 66:494–498.PubMedGoogle Scholar
  155. Vicart P, Caron A, Guicheney P, Li Z, Prevost MC, Faure A, Chateau D, Chapon F, Tome F, Dupret JM, Paulin D, Fardeau M (1998) A missense mutation in the alphaB-crystallin chaperone gene causes a desmin-related myopathy. Nat Genet 20:92–95.PubMedGoogle Scholar
  156. Wilson SP, Al-Sarraj S, Bridges LR (1996) Rosenthal fiber encephalopathy presenting with demyelination and Rosenthal fibers in a solvent abuser: adult Alexander’s disease? Clin Neuropathol 15:13–16.PubMedGoogle Scholar
  157. Wippold FJ IIPerry A, Lennerz J (2006) Neuropathology for the neuroradiologist: Rosenthal fibers. AJNR Am J Neuroradiol 27:958–961.PubMedGoogle Scholar
  158. Wu KC, Bryan JT, Morasso MI, Jang SI, Lee JH, Yang JM, Marekov LN, Parry DA, Steinert PM (2000) Coiled-coil trigger motifs in the 1B and 2B rod domain segments are required for the stability of keratin intermediate filaments. Mol Biol Cell 11:3539–3558.PubMedGoogle Scholar
  159. Wu Y, Jiang YW, Wang JM, Yang YL, Zhang YH, Chang XZ, Qin J, Xiao JX, Wu X (2006) GFAP mutations in 3 Chinese infantile Alexander disease patients. J Inherit Metab Dis 29:66.Google Scholar
  160. Zatloukal K, Stumptner C, Fuchsbichler A, Heid H, Schnoelzer M, Kenner L, Kleinert R, Prinz M, Aguzzi A, Denk H (2002) p62 Is a common component of cytoplasmic inclusions in protein aggregation diseases. Am J Pathol 160:255–263.PubMedGoogle Scholar
  161. Zhang X, Haaf M, Todorich B, Grosstephan E, Schieremberg H, Surguladze N, Connor JR (2005) Cytokine toxicity to oligodendrocyte precursors is mediated by iron. Glia 52:199–208.PubMedGoogle Scholar
  162. Zlotogora J (1998) Germ line mosaicism. Hum Genet 102:381–386.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Michael Brenner
    • 1
  • James E. Goldman
    • 1
  • Roy A. Quinlan
    • 1
  • Albee Messing
    • 1
  1. 1.Department of NeurobiologyEvelyn F. McKnight Brain Institute, Center for Glial Biology in Medicine, University of Alabama BirminghamBirminghamUSA

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