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Journal Information
Vol. 33. Issue 8.
Pages 526-533 (October 2018)
Vol. 33. Issue 8.
Pages 526-533 (October 2018)
Review article
DOI: 10.1016/j.nrleng.2017.01.006
Open Access
Myelin changes in Alexander disease
La alteración de la mielina en la enfermedad de Alexander
U. Gómez-Pinedoa,
Corresponding author
, M. Duran-Morenob, S. Sirerol-Piquerb, J. Matias-Guiua
a Laboratorio de Neurobiología, Servicio de Neurología, Instituto de Neurociencias, IdISSC, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, Spain
b Laboratorio de Neurobiología Comparada, Instituto Cavanilles de Biodiversidad y Biología Evolutiva, Universidad de Valencia, Valencia, Spain
Article information
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Alexander disease (AxD) is a type of leukodystrophy. Its pathological basis, along with myelin loss, is the appearance of Rosenthal bodies, which are cytoplasmic inclusions in astrocytes. Mutations in the gene coding for glial fibrillary acidic protein (GFAP) have been identified as a genetic basis for AxD. However, the mechanism by which these variants produce the disease is not understood.


The most widespread hypothesis is that AxD develops when a gain-of-function mutation causes an increase in GFAP. However, this mechanism does not explain myelin loss, given that experimental models in which GFAP expression is normal or mutated do not exhibit myelin disorders. This review analyses other possibilities that may explain this alteration, such as epigenetic or inflammatory alterations, presence of NG2 (+) – GFAP (+) cells, or post-translational modifications in GFAP that are unrelated to increased expression.


The different hypotheses analysed here may explain the myelin alteration affecting these patients; several of these mechanisms may co-occur. These theories raise the possibility of designing therapies based on these mechanisms.

Alexander disease
Glial fibrillar acidic protein
Chondroitin sulfate proteoglycan-NG2

La enfermedad de Alexander (AxD) es una leucodistrofia. Su base patológica, junto a la pérdida de mielina, es la aparición de los cuerpos de Rosenthal, que son inclusiones citoplasmáticas en células astrocitarias. Mutaciones en el gen que codifica la GFAP se han identificado como una base genética para AxD. Sin embargo, no se conoce el mecanismo por el cual estas variantes producen la enfermedad.


La hipótesis más extendida es que AxD se desarrolla por un mecanismo por ganancia de función debido al incremento de GFAP. Sin embargo, este mecanismo no explica la pérdida mielínica, dado que los modelos experimentales que expresan GFAP normal o mutada no generan alteración mielínica. En la presente revisión se analizan otras posibilidades que permitan justificar dicha alteración, como son alteraciones epigenéticas, inflamatorias, la existencia de células NG2 (+)-GFAP (+) o cambios postraslacionales sobre la GFAP al margen de la mayor expresión.


Las diferentes hipótesis analizadas pueden explicar la alteración de la mielina que aparece en los pacientes y que pueden presentarse asociadas y abren la posibilidad de plantear terapéuticas basadas en estos mecanismos.

Palabras clave:
Enfermedad de Alexander
Proteína acidica fibrilar glial
Condroitín sulfato proteoglicano-NG2
Full Text

Alexander disease (AxD), named after the physician who first described it in 1949,1 is a leukodystrophy causing the destruction of myelin. In addition to myelin loss, the pathophysiology of the disease involves the formation of Rosenthal fibres,2 cytoplasmic inclusions within glial cells that have also been observed in some gliomas. These inclusions are formed by glial fibrillary acidic protein (GFAP), α–β crystallin, and heat shock protein 27 (HSP27),3,4 although other proteins such as vimentin, p62, and plectin have also been reported.5 From a clinical viewpoint, the disease has three different forms: infantile, juvenile, and adult; the infantile form has the poorest prognosis.6–8 Mutations in the GFAP gene constitute the genetic basis of AxD. These mutations, constituting changes in 32 specific nucleotides, are present in both familial and sporadic cases.9,10 However, we are yet to determine the mechanism by which these mutations cause GFAP aggregation within astrocytes, the way in which GFAP expressed by astrocytes contributes to symptoms, and especially the mechanism of demyelination. Radiology studies reveal periventricular demyelination11; patients with long survival times display extremely severe demyelination, affecting nearly all the white matter.12

GFAP, first isolated and described by Eng in 1969,13 is a component of the intermediate filaments found in astrocytes, together with vimentin and nestin. In addition to playing a structural role in astrocytes, where together with microtubules and microfilaments they form the cytoskeleton, these filaments are also involved in signal transmission. GFAP is also present in other central nervous system (CNS) cells, such as ependymal cells, in non-myelin-producing Schwann cells of the peripheral nervous system, and in enteric glia.

The protein is encoded by a single gene located on 17q21, which contains nine exons. At least 10 isoforms result from alternative splicing of GFAP pre-mRNA and the polyadenylation signal.14–17 GFAP-α (isoform 1) is the predominant isoform in the brain and spinal cord, but it also appears in the peripheral nervous system; it contains the classic 432 residues with full usage of the 9 exons of the GFAP gene. GFAP-δ or GFAP-?? (isoform 2) is preferentially expressed by astrocytes from neurogenic niches including the subventricular zone and the hippocampus. GFAP-δ includes the use of an intron before exon 8 and has an alternative C-terminus and 431 residues. GFAP-δ is expressed in reactive astrocytes in diseases such as epilepsy, Alzheimer disease, and gliomas. The remaining isoforms are less frequent, although the association between some of these variants and neurodegenerative diseases has made them a subject of considerable research interest.18,19

Myelin is produced by oligodendrocytes in a dynamic process requiring 3 conditions: the presence of oligodendrocyte precursor cells (OPCs) in the demyelinated area, changes in oligodendrocyte form and membranes, and a favourable microenvironment. OPCs are immature oligodendrocytes that remain in the adult brain after embryonic development. They account for 5%-8% of the population of CNS glial cells20 and contribute to restoration of the myelin sheath, differentiating throughout adulthood. OPCs can express proteins including Olig2 and NG2. Myelin proteins produced and accumulated as a result of demyelination prevent remyelination through the protein kinase C α, Nogo 1, or LINGO1 signalling pathways.21,22 Semaphorins also play a role in regulating remyelination.23 Consequently, demyelination in patients with AxD may be explained by mechanisms with at least 4 effects24: (1) OPCs not being generated or surviving; (2) absence of stimuli promoting oligodendrocyte maturation; (3) prevention of myelin production by local inhibitory factors; or (4) presence of axonal alterations preventing myelination. This review analyses the hypotheses explaining myelin changes in patients with AxD.

Gain-of-function mechanism in the glial fibrillary acidic protein

Cho and Messing25 suggest that AxD is due to GFAP accumulation in astrocytes and that high levels of both mutant and wild-type GFAP are damaging. They propose a gain-of-function mechanism similar to that proposed for other neurodegenerative diseases, for example, in SOD1-dependent forms of amyotrophic lateral sclerosis.26 This mechanism is controversial, however.27 GFAP aggregates sequester HSP27, cathepsin, and α–βcrystallin; subsequent phosphorylation and ubiquitination generates Rosenthal fibres, triggering astrocyte damage28 and the activation of stress response pathways, such as the JNK and p38 pathways, in these astrocytes.29–31 Decreased GFAP degradation may be associated with decreased proteasome activity.32 Given GFAP's long half-life in vivo, interfering with protein degradation may have a prolonged effect, contributing to GFAP accumulation.33 This hypothesis has generated a considerable number of experiments and models, especially in mice with hyperexpression of mutant or wild-type GFAP. Tanaka et al.34 have published a study on transgenic mice with an R239H mutation. Messing and colleagues have studied 2 mouse models reproducing Rosenthal fibres and GFAP accumulation. These models provide valuable data on the mechanisms triggered by GFAP accumulation.35–40 Other researchers have attempted to establish a correlation between disease prognosis and CSF GFAP level.41 The main weakness of this hypothesis is that this mechanism does not cause demyelination42 (Fig. 1A). A further limitation is the fact that gliomas displaying GFAP accumulation and Rosenthal fibres do not show myelin loss; it is therefore reasonable to question the assertion that increased GFAP levels alone may explain the disease.

Figure 1.

Schematic representation of the hypotheses explaining myelin changes in AxD. (A) Gain-of-function mechanism. (B) Epigenetic alterations on transcription. (C) The inflammatory mechanism. (D) GFAP+/NG2+ cells. (E) Post-transcriptional alterations of GFAP.

Epigenetic alterations to transcription

GFAP expression levels are regulated by the activity of the GFAP gene promoter; this process is largely dependent on epigenetic alterations. During astrogenesis in neural stem cells, GFAP promoter demethylation activates GFAP transcription43–46; histone acetylation controls GFAP expression during neural stem-cell differentiation and depends on the cell's stage of differentiation.47,48 The degree of histone acetylation is regulated by the enzyme's histone acetylase and histone deacetylase (HDAC). Kanski et al.49 have shown that histone acetylation in astrocytes is an important regulator of the transcription and alternative splicing of GFAP. HDAC inhibition significantly reduces GFAP expression in primary human astrocytes and in astrocytoma cells. This mechanism is noteworthy given that HDAC inhibition modifies the balance between alternative transcription of GFAP-δ and the constitutive isoform GFAP-α, favouring GFAP-δ expression, which is modified during differentiation into astrocyte or oligodendrocyte lineage cells. Inhibition of HDAC activity modifies the structure of intracellular GFAP filaments in terms of length, location, and degree of aggregation. Several studies have found an association between changes in GFAP aggregation and alterations in differentiation in patients with leukodystrophies,50–52 associated with differences in GFAP-δ expression. The literature includes a report of a patient with mutations in GFAP and HDAC6 who had a severe phenotype of AxD53 and showed reduced HDAC6 activity. According to these authors’ hypothesis, myelin loss in AxD is explained by GFAP aggregation and alterations in oligodendrocyte differentiation (Fig. 1B).

The inflammatory mechanism

Olabarria et al.54 suggest that AxD may be mediated by an inflammatory mechanism. The demyelination observed in multiple sclerosis and neuromyelitis optica is of autoimmune origin and partly attributable to inflammatory mechanisms and increased levels of proinflammatory cytokines. Kondo et al.55 studied induced pluripotent stem cells (iPSCs) from 3 patients with AxD and different GFAP mutations. AxD iPSC-derived astrocytes showed GFAP+ cytoplasmic aggregates, such as Rosenthal fibres, and altered cytokine release. Some authors report moderate lymphocytic infiltration and microglial activation in the brains of patients with AxD.56,57 These authors have studied cytokine expression in mouse models with GFAP overexpression and mice heterozygous for the GFAP-R236H mutation, detecting an inflammatory response. The iPSCs taken from the patients with AxD showed increased levels of proinflammatory cytokines such as GM-CSF, IL-5, IL-6, and tumour necrosis factor-α. It has also been reported that the GFAP molecule may be deaminated,58 which may trigger an autoimmune response.59 In light of the above, these authors suggest that a neuroinflammatory process may be involved in AxD pathogenesis and that myelin loss may be due to an autoimmune mechanism, as occurs with multiple sclerosis (Fig. 1C).

GFAP+/NG2+ cells

NG2+ glial cells,60,61 also known as synantocytes62 or polydendrocytes,63 represent 8%-9% of all white matter cells and 2%-3% of grey matter cells.64 They were initially identified as Olig2 progenitor cells65 as they differentiated into oligodendrocytes.66–70 NG2+ glial cells are in fact OPCs capable of receiving synaptic input, therefore regulating their own differentiation. These cells can also extend their processes to the node of Ranvier and transform into reactive astrocytes in pathological conditions and in cell cultures71,72; they therefore represent a transitional stage between olygodendrocytes and astrocytes.73 NG2+ cells may be GFAP+ in certain pathological conditions or locations, such as the area surrounding the demyelination in multiple sclerosis.74 Oligodendrocyte lineage cells have also been found to be GFAP+ in patients with leukodystrophies and autoimmune or virus-induced myelin alterations.75–77 Mice with overexpression of mutant GFAP display altered hippocampal neurogenesis.78 Our research group observed the same findings in a cell model transfected with AxD mutations.79 GFAP expression makes Schwann cells behave functionally as astrocytes, not generating myelin.80 GFAP expression has been observed in oligodendroglial lineage cells in the initial stages; NG2 expression has been observed in cells that will subsequently differentiate into astrocytes81–84; copresence of GFAP and NG2 expression makes it very difficult to determine whether cells are oligodendrocytes or astrocytes. OPC transplantation into the CNS generates oligodendrocytes and astrocytes simultaneously.85 Persistence of GFAP expression in cells that should differentiate into oligodendrocyte lineage cells would explain GFAP accumulation and the absence of myelin production (Fig. 1D). Persistence of GFAP expression in NG2+ cells, and consequently differentiation into a specific lineage, is very likely to depend on the GFAP isoform or on factors related to the microenvironment where maturation occurs.

Post-transcriptional alterations of GFAP

Astrocytes secrete high levels of neurotrophic factors,86 some of which are involved in myelination. Some experimental models have shown that BDNF is involved in oligodendrocyte proliferation and in remyelination.87,88 The interaction between astrocytes and oligodendrocytes may play a crucial role in myelination.89,90 Experiments with cell cultures provide direct evidence that BDNF in astrocytes promotes OPC maturation; in vivo studies have observed reduced oligodendrogenesis in transgenic mice showing reduced astrocytic BDNF regulation. Other growth factors, including CNTF,91 FGF, TGF, and GDNF, as well as nuclear receptors, may modify the activation of GFAP transcription.92 Yang and Wang93 extensively reviewed the complex mechanisms occurring after GFAP transcription. GFAP undergoes a series of post-translational changes and is highly regulated by protein kinases; some genetic and environmental changes affecting the molecule may have an impact on astrocyte function, altering myelination (Fig. 1E).


The hypothesis of the gain-of-function mechanism suggests the possibility that we may discover a drug that could improve patients’ condition by reducing GFAP expression. Great efforts have been made to develop effective treatments with cell or mouse models of GFAP hyperexpression.94,95 However, if the changes induced by GFAP hyperexpression are secondary, such treatments would be symptomatic, and therefore insufficient for a disease starting during embryonic development or the neonatal period.

The different hypotheses discussed may explain myelin alterations in patients with AxD; some of these mechanisms may co-occur. Administering treatments capable of modifying the epigenetic mechanisms of the disease96 is a reasonable and entirely valid option; this line of treatment is already being evaluated in clinical trials in the context of cancer.97 Likewise, the differentiation of immature cells into astrocyte and oligodendrocyte lineage cells may constitute another therapeutic target.

Conflicts of interest

The authors have no financial or commercial relationships that could create conflicts of interest with regard to this article.


We would like to thank the Ayuda Juanma Foundation (www.ayudajuanma.es) for funding research into AxD at Hospital Clínico San Carlos.

W.S. Alexander.
Progressive fibrinoid degeneration of fibrillary astrocytes associated with mental retardation in a hydrocephalic infant.
Brain, 72 (1949), pp. 373-381
I.I. Wippold, A. Perry, J. Lennerz.
Neuropathology for the neurologist: Rosenthal fibers.
Am J Neuroradiol, 27 (2006), pp. 9508-9961
N. Tomokane, T. Iwaki, J. Tateishi, A. Awaki, J.E. Goldman.
Rosenthal fibers share epitopes with alfa-B-crystallin, glial fibrillary acid protein and ubiquitin, but not vimentin: immunoelectron microscopy with colloidal gold.
Am J Pathol, 138 (1991), pp. 875-885
M.W. Head, E. Corbin, J.E. Goldman.
Overexpression an abnormal modification of the stress proteins alpha-B-crystallin and HSP27 in Alexander disease.
Am J Pathol, 143 (1993), pp. 1743-1753
K. Zatloukal, C. Stumptner, A. Fuchsbichler, H. Heid, M. Schnoelzer, L. Kenner, et al.
p62 is a common component of cytoplasmic inclusions in protein aggregation diseases.
Am J Pathol, 160 (2002), pp. 255-263
L.S. Russo, A. Aron, P.J. Anderson.
Alexander's disease: a report and reprassail.
Neurology, 26 (1976), pp. 607-614
J.W. Neal, E.M. Cave, S.K. Singhrao, G. Cole, S.L. Wallace.
Alexander's disease in infancy and childhood: a report of two cases.
Acta Neuropathol, 84 (1992), pp. 322-327
M. Deprez, M. d’Hooghe, J.P. Misson, I. de Leval, C. Ceuterick, M. Reznik, et al.
Infantile and juvenile presentation of Alexander's disease: a report of two cases.
Acta Neurol Scand, 99 (1999), pp. 158-165
R. Li, A.B. Johnson, G. Salomons, J.E. Goldman, S. Naidu, R. Quinlan, et al.
Glial fibrillary acidic proteins mutations in infantile, juvenile, and adult forms of Alexander's disease.
Ann Neurol, 53 (2005), pp. 310-326
R. Li, A.B. Johnson, G.S. Salomons, M.S. Van der Knaap, D. Rodriguez, O. Boespflug-Tamguy, et al.
Propensity for pattern inherence of the novo mutations in Alexander's disease.
Hum Genet, 119 (2006), pp. 137-144
M.S. Van der Knaap, S. Naidu, S.N. Breiter, S. Blaser, H. Stroink, S. Springer.
Alexander disease: diagnosis with MR imaging.
Am J Neuroradiol, 22 (2001), pp. 541-552
T. Shiihara, T. Yoneda, I. Mizuta, T. Yoshida, M. Nakagawa, N. Shimizu.
Serial MRI changes in a patient with infantile Alexander disease and prolonged survival.
Brain Dev, 33 (2011), pp. 604-607
L.F. Eng, R.S. Ghirnikar, Y.L. Lee.
Glial fibrillary acidic protein: GFAP-thirty-one years (1969–2000).
Neurochem Res, 25 (2000), pp. 1439-1451
E.M. Hol, R.F. Roelofs, E. Moraal, M.A. Sonnemans, J.A. Sluijs, A.E. Proper, et al.
Neuronal expression of GFAP in patients with Alzheimer pathology and identification of novel GFAP splice forms.
Mol Psychiat, 8 (2003), pp. 786-796
J. Blechingberg, S. Lykke-Andersen, T.H. Jensen, A.L. Jorgensen, A.L. Nielsen.
Regulatory mechanisms for 3′-end alternative splicing and polyadenylation of the glial fibrillary acidic protein, GFAP, transcript.
Nucleic Acids Res, 35 (2007), pp. 7636-7650
A.L. Nielsen, I.E. Holm, M. Johansen, B. Bonven, P. Jorgensen, A.L. Jorgensen.
A new splice variant of glial fibrillary acidic protein, GFAP epsilon, interacts with the presenilin proteins.
J Biol Chem, 277 (2002), pp. 29983-29991
W. Kamphuis, C. Mamber, M. Moeton, L. Kooijman, J.A. Sluijs, A.H. Jansen, et al.
GFAP isoforms in adult mouse brain with a focus on neurogenic astrocytes and reactive astrogliosis in mouse models of Alzheimer disease.
W. Kamphuis, J. Middeldorp, L. Kooijman, J.A. Sluijs, E.J. Kooi, M. Moeton, et al.
Glial fibrillary acidic protein isoform expression in plaque related astrogliosis in Alzheimer's disease.
Neurobiol Aging, 35 (2014), pp. 492-510
E.M. Hol, R.F. Roelofs, E. Moraal, M.A. Sonnemans, J.A. Sluijs, E.A. Proper, et al.
Neuronal expression of GFAP in patients with Alzheimer pathology and identification of novel GFAP splice forms.
Mol Psychiat, 8 (2003), pp. 786-796
J.M. Levine, R. Reynolds, J.W. Fawcett.
The oligodendrocyte precursor cell in health and disease.
Trends Neurosci, 24 (2001), pp. 39-47
L.W. Lau, R. Cua, M.B. Keough, S. Haylock-Jacobs, V.W. Yong.
Pathophysiology of the brain extracellular matrix: a new target for remyelination.
Nat Rev Neurosci, 14 (2013), pp. 722-729
D.E. Harlow, W.B. Macklin.
Inhibitors of myelination: ECM changes, CSPGs and PTPs.
A. Sandvig, M. Berry, L.B. Barrett, A. Butt, A. Logan.
Myelin-, reactive glia-, and scar-derived CNS axon growth inhibitors: expression, receptor signaling, and correlation with axon regeneration.
Glia, 46 (2004), pp. 225-251
J. Matías-Guiu, U. Gomez-Pinedo, J.A. Matias-Guiu.
News in multiple sclerosis: remyelination as a therapeutic target.
W. Cho, A. Messing.
Properties of astrocytes cultured from GFAP over-expressing and GFAP mutant mice.
Exp Cell Res, 315 (2009), pp. 1260-1272
J. Matias-Guiu, L. Galan, R. Garcia-Ramos, J.A. Barcia.
Superoxide dismutase: the cause of all amyotrophic lateral sclerosis?.
Ann Neurol, 64 (2008), pp. 356-357
U. Gómez-Pinedo, R.N. Villar-Quiles, L. Galán, J.A. Matías-Guiu, M.S. Benito-Martin, A. Guerrero-Sola, et al.
Immununochemical markers of the amyloid cascade in the hippocampus in motor neuron diseases.
Front Neurol, 7 (2016), pp. 195
M. Der Perng, M. Su, S. Fang Wen, R. Li, T. Gibbon, A.R. Prescott, et al.
The Alexander disease-causing glial fibrillary acid protein mutant, R416W, accumulates into Rosenthal fibers by a pathway that involves filament aggregation and the association of alfa-B cristralin and HSP 27.
Am J Hum Gen, 79 (2006), pp. 197-213
T.L. Hagemann, J.X. Connor, A. Messing.
Alexander disease-associated glial fibrillary acidic protein mutations in mice induce Rosenthal fiber formation and a white matter stress response.
J Neurosci, 26 (2006), pp. 11162-11173
T.L. Hagemann, S.A. Gaeta, M.A. Smith, D.A. Johnson, J.A. Johnson, A. Messing.
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 (2005), pp. 2443-2458
G. Tang, Z. Xu, J.E. Goldman.
Synergistic effects of the SAPK/JNK and the proteasome pathway on glial fibrillary acidic protein (GFAP) accumulation in Alexander disease.
J Biol Chem, 281 (2006), pp. 38634-38643
R.A. Quintan, M. Brenner, J.E. Goldman, A. Messing.
GFAP and its role in Alexander disease.
Exp Clin Res, 313 (2007), pp. 2077-2087
R.K. Liem, A. Messing.
Dysfunctions of neuronal and glial intermediate filaments in disease.
J Clin Invest, 119 (2009), pp. 1814-1824
K.H. Tanaka, H. Takebayashi, Y. Yamazaki, K. Ono, M. Naruse, T. Iwasato, et al.
Murine model of Alexander disease: analysis of GFAP aggregate formation and its pathological significance.
Glia, 55 (2007), pp. 617-631
R. Tian, M. Gregor, G. Wiche, J.E. Goldman.
Plectin regulates the organization of glial fibrillary acidic protein in Alexander disease.
Am J Pathol, 168 (2006), pp. 888-897
T.L. Hagemann, E.M. Jobe, A. Messing.
Genetic ablation of Nrf2/antioxidant response pathway in Alexander disease mice reduces hippocampal gliosis but does not impact survival.
C.M. LaPash Daniels, E.V. Austin, D.E. Rockney, E.M. Jacka, T.L. Hagemann, D.A. Johnson, et al.
Beneficial effects of Nrf2 overexpression in a mouse model of Alexander disease.
J Neurosci, 32 (2012), pp. 10507-10515
G. Tang, Z. Xu, J.E. Goldman.
Synergic effects of the SAPK/JNK and the proteosome pathway on glial fibrillary acidic protein (GFAP) accumulation in Alexander disease.
J Biol Chem, 281 (2006), pp. 38634-38643
M.H. Chen, T.L. Hagemann, R.A. Quinlan, A.B. Messing, M.D. Perng.
Caspase cleavage of GAP produces an assembly-compromised proteolytic fragment that promotes filament aggregation.
ASN Neurol, 5 (2013), pp. e00125
T.W. Meisingset, O. Risa, M. Brenner, A. Messing, U. Sonnewald.
Alteration of glial–neuronal metabolic interactions in a mouse model of Alexander disease.
Glia, 58 (2010), pp. 1228-1234
P.L. Jany, G.E. Agosta, W.S. Benko, J.C. Eickhoff, S.R. Keller, W. Köehler, et al.
CSF and blood levels of GFAP in Alexander disease.
eNeuro, 5 (2015), pp. 2
T.L. Hagemann, J.X. Connor, A. Messing.
Alexander disease-associated glial fibrillary acidic protein mutations in mice induced Rosenthal fiber formation and a white matter stress response.
J Neurosci, 26 (2006), pp. 11162-11173
T. Takizawa, K. Nakashima, M. Namihira, W. Ochiai, A. Uemura, Yanagisawa, et al.
DNA methylation is a critical cell-intrinsic determinant of astrocyte differentiation in the fetal brain.
Dev Cell, 1 (2001), pp. 749-758
G. Fan, K. Martinowich, M.H. Chin, F. He, S.D. Fouse, L. Hutnick, et al.
DNA methylation controls the timing of astrogliogenesis through regulation of JAK-STAT signaling.
Develop, 132 (2005), pp. 3345-3356
M. Namihira, J. Kohyama, K. Semi, T. Sanosaka, B. Deneen, T. Taga, et al.
Committed neuronal precursors confer astrocytic potential on residual neural precursor cells.
Dev Cell, 16 (2009), pp. 245-255
R. Kanski, M.E. van Strien, P. van Tijn, E.M. Hol.
A star is born: new insights into the mechanism of astrogenesis.
Cell Mol Life Sci, 71 (2014), pp. 433-447
H. Asano, M. Aonuma, T. Sanosaka, J. Kohyama, M. Namihira, K. Nakashima.
Astrocyte differentiation of neural precursor cells is enhanced by retinoic acid through a change in epigenetic modification.
Stem Cells, 27 (2009), pp. 2744-2752
Q. Zhou, C.L. Dalgard, C. Wynder, M.L. Doughty.
Histone deacetylase inhibitors SAHA and sodium butyrate block G1-to-S cell cycle progression in neurosphere formation by adult subventricular cells.
BMC Neurosci, 12 (2011), pp. 50
R. Kanski, M.A. Sneeboer, E.J. van Bodegraven, J.A. Sluijs, W. Kropff, M.W. Vermunt, et al.
Histone acetylation in astrocytes suppresses GFAP and stimulates a reorganization of the intermediate filament network.
J Cell Sci, 127 (2014), pp. 4368-4380
C. Mignot, O. Boespflug-Tanguy, A. Gelot, A. Dautigny, D. Pham-Dinh, D. Rodriguez.
Alexander disease: putative mechanisms of an astrocytic encephalopathy.
Cell Mol Life Sci, 61 (2004), pp. 369-385
M. Bugiani, I. Boor, B. van Kollenburg, N. Postma, E. Polder, C. van Berkel, et al.
Defective glial maturation in vanishing white matter disease.
J Neuropathol Exp Neurol, 70 (2011), pp. 69-82
A. Huyghe, L. Horzinski, A. Hénaut, M. Gaillard, E. Bertini, R. Schiffmann, et al.
Developmental splicing deregulation in leukodystrophies related to EIF2B mutations.
L. Melchionda, M. Fang, H. Wang, V. Fugnanesi, M. Morbin, X. Liu, et al.
Adult-onset Alexander disease, associated with a mutation in an alternative GFAP transcript, may be phenotypically modulated by a non-neutral HDAC6 variant.
Orphanet J Rare Dis, 8 (2013), pp. 66
M. Olabarria, M. Putilina, E.C. Riemer, J.E. Goldman.
Astrocyte pathology in Alexander disease causes a marked inflammatory environment.
Acta Neuropathol, 130 (2015), pp. 469-486
T. Kondo, M. Funayama, M. Miyake, K. Tsukita, T. Era, H. Osaka, et al.
Modeling Alexander disease with patient iPSCs reveals cellular and molecular pathology of astrocytes.
Acta Neuropathol Commun, 4 (2016), pp. 69
L.S.J. Russo, A. Aron, P.J. Anderson.
Alexander's disease: a report and reappraisal.
Neurology, 26 (1976), pp. 607-614
J. Towfighi, R. Young, J. Sassani, J. Ramer, D.S. Horoupian.
Alexander's disease: further light-, and electron-microscopic observations.
Acta Neuropathol, 61 (1983), pp. 36-42
B. György, E. Tóth, E. Tarcsa, A. Falus, E.I. Buzás.
Citrullination: a posttranslational modification in health and disease.
Int J Biochem Cell Biol, 38 (2006), pp. 1662-1677
V. Romero, J. Fert-Bober, P.A. Nigrovic, E. Darrah, U.J. Haque, D.M. Lee, et al.
Immune-mediated pore-forming pathways induce cellular hypercitrullination and generate citrullinated autoantigens in rheumatoid arthritis.
Sci Transl Med, 5 (2013),
A. Nishiyama, Z. Yang, A. Butt.
Astrocytes and NG2-glia: what's in a name?.
R. Wigley, N. Hamilton, A. Nishiyama, F. Kirchhoff, A.M. Butt.
Morphological and physiological interactions of NG2-glia with astrocytes and neurons.
A.M. Butt, N. Hamilton, P. Hubbard, M. Pugh, M. Ibrahim.
Synantocytes: the fifth element.
A. Nishiyama.
Polidendrocytes: NG2 cells with many roles in development and repair in CNS.
Neuroscientist, 1 (2007), pp. 62-76
M.R. Dawson, A. Polito, J.M. Levine, R. Reynolds.
NG2-expressing glial progenitor cells: an abundant and widespread population of cycling cells in the adult rat CNS.
Mol Cell Neurosci, 24 (2003), pp. 476-488
M.C. Raff, R.H. Miller, M. Noble.
A glial progenitor cell that develops in vitro into an astrocyte or an oligodendrocyte depending on culture medium.
Nature, 303 (1983), pp. 390-396
P.J. Horner, A.E. Power, G. Kempermann, H.G. Kuhn, T.D. Palmer, J. Winkler, et al.
Proliferation and differentiation of progenitor cells throughout the intact adult rat spinal cord.
J Neurosci, 20 (2000), pp. 2218-2228
A. Nishiyama, M. Watanabe, Z. Yang, J. Bu.
Identity, distribution, and development of oligodendrocytes: NG2-expressing glial cells.
J Neurocytol, 31 (2002), pp. 437-455
J. Bu, A. Banki, Q. Wu, A. Nishiyama.
Increased NG2+ glial cell proliferation and oligodendrocyte generation in the hypomyelinating mutant shiverer.
Glia, 48 (2004), pp. 51-63
R. Reynolds, M. Dawson, D. Papadopoulos, A. Polito, I.C. di Bello, D. Pham-Dinh, et al.
The response of NG2-expressing oligodendrocyte progenitors to demyelination in MOG-EAE and MS.
J Neurocytol, 31 (2002), pp. 523-536
A. Polito, R. Reynolds.
NG2-expressing cells as oligodendrocyte progenitors in the normal and demyelinated adult central nervous system.
G. Leoni, M. Rattray, A.M. Butt.
NG2 cells differentiate into astrocytes in cerebellar slices.
Mol Cell Neurosci, 42 (2009), pp. 208-218
P. Honsa, H. Pivonkova, D. Dzamba, M. Filipova, M. Anderova.
Polydendrocytes display large lineage plasticity following focal cerebral ischemia.
X. Zhu, D.E. Bergles, A. Nishiyama.
NG2 cells generate both oligodendrocytes and gray matter astrocytes.
Development, 135 (2008), pp. 145-157
A. Nair, T.J. Frederick, S.D. Miller.
Astrocytes in multiple sclerosis: a product of their environment.
Cell Mol Life Sci, 65 (2008), pp. 2702-2720
C. Godfraind, V.L. Friedrich, K.V. Holmes, M. Dubois-Dalcq.
Dubois-Dalcq: in vivo analysis of glial cell phenotypes during a viral demyelinating disease in mice.
J Cell Biol, 109 (1989), pp. 2405-2416
W.M. Carroll, A.R. Jennings, F.L. Mastaglia.
Reactive glial cells in CNS demyelination contain both GC and GFAP.
Brain Res, 411 (1987), pp. 364-369
C.A. Dyer, A. Kendler, T. Philibotte, P. Gardiner, J. Cruz, H.L. Levy.
Evidence for central nervous system glial cell plasticity in phenylketonuria.
J Neuropathol Exp Neurol, 55 (1966), pp. 795-814
T.L. Hagemann, R. Paylor, A. Messing.
Deficits in adult neurogenesis, contextual fear conditioning, and spatial learning in a Gfap mutant mouse model of Alexander disease.
J Neurosci, 33 (2013), pp. 18698-18706
Duran M. Efecto de las mutaciones de GFAP sobre la diferenciación de la estirpe oligodendrocitaria. TFM Direccion, JM Garcia-Verdugo, J Matias-Guiu. Trabajo de Fin de Master, Universidad de Valencia, España, 2011.
K. Mokuno, J. Kamholz, T. Behrman, C. Black, M. Sessa, D. Feinstein, et al.
Neuronal modulation of Schwann cell glial fibrillary acidic protein (GFAP).
J Neurosci Res, 23 (1989), pp. 396-405
B. Alghamdi, R. Fern.
Phenotype overlap in glial cell populations: astroglia, oligodendroglia and NG-2(+) cells.
Front Neuroanat, 9 (2015), pp. 49
B.H. Choi, R.C. Kim.
Expression of glial fibrillary acidic protein in immature oligodendroglia.
Science, 223 (1984), pp. 407-409
B.H. Choi, R.C. Kim.
Expression of glial fibrillary acidic protein by immature oligodendroglia and its implications.
J Neuroimmunol, 8 (1985), pp. 215-235
B.H. Choi.
Glial fibrillary acidic protein in radial glia of early human-fetal cerebrum—a light and electron-microscopic immunoperoxidase study.
J Neuropathol Exp Neurol, 45 (1986), pp. 408-418
M.S. Windrem, M.C. Nunes, W.K. Rashbaum, T.H. Schwartz, R.A. Goodman, G. McKhann II, et al.
Fetal and adult human oligodendrocyte progenitor cell isolates myelinate the congenitally dysmyelinated brain.
Nat Med, 10 (2004), pp. 93-97
T. Guillamón-Vivancos, U. Gómez-Pinedo, J. Matías-Guiu.
Astrocytes in neurodegenerative diseases: function and molecular description.
Neurologia, 30 (2015), pp. 119-129
J. Ramos-Cejudo, M. Gutiérrez-Fernández, L. Otero-Ortega, B. Rodríguez-Frutos, B. Fuentes, M.T. Vallejo-Cremades, et al.
Brain-derived neurotrophic factor administration mediated oligodendrocyte differentiation and myelin formation in subcortical ischemic stroke.
C.G. Fulmer, M.W. vonDran, A.A. Stillman, Y. Huang, B.L. Hempstead, C.F. Dreyfus.
Astrocyte-derived BDNF supports myelin protein synthesis after cuprizone-induced demyelination.
J Neurosci, 34 (2014), pp. 8186-8196
N. Miyamoto, T. Maki, A. Shindo, A.C. Liang, M. Maeda, N. Egawa, et al.
Astrocytes promote oligodendrogenesis after white matter damage via brain-derived neurotrophic factor.
J Neurosci, 35 (2015), pp. 14002-14008
S. Djalali, M. Höltje, G. Grosse, T. Rothe, T. Stroh, J. Grosse, et al.
Effects of brain-derived neurotrophic factor (BDNF) on glial cells and serotonergic neurones during development.
J Neurochem, 92 (2005), pp. 616-627
S.W. Levison, S.N. Hudgins, J.L. Crawford.
Ciliary neurotrophic factor stimulates nuclear hypertrophy and increases the GFAP content of cultured astrocytes.
Brain Res, 803 (1998), pp. 189-193
A. Uzdensky, M. Komandirov, G. Fedorenko, A. Lobanov.
Protection effect of GDNF and neurturin on photosensitized crayfish neurons and glial cells.
J Mol Neurosci, 49 (2012), pp. 480-490
Z. Yang, K.K. Wang.
Glial fibrillary acid protein: from intermediate filament assembly and gliosis to neurobiomarker.
Trends Neurosci, 38 (2015), pp. 364-374
W. Cho, M. Brenner, N. Peters, A. Messing.
Drug screening to identify suppressors of GFAP expression.
Hum Mol Genet, 9 (2010), pp. 3169-3178
T. Bachetti, E. di Zanni, P. Balbi, P. Bocca, I. Prigione, G.A. Deiana, et al.
In vitro treatments with ceftriaxone promote elimination of mutant glial fibrillary acidic protein and transcription down-regulation.
Exp Cell Res, 316 (2010), pp. 2152-2165
E. Afshinnekoo, C.E. Mason.
Epigenetic therapy in a new era of medicine: creating and integrating molecular profiles of patients.
Ann Transl Med, 4 (2016), pp. 436
S.H. Song, S.W. Han, Y.J. Bang.
Epigenetic-based therapies in cancer: progress to date.

Please cite this article as: Gómez-Pinedo U, Duran-Moreno M, Sirerol-Piquer S, Matias-Guiu J. La alteración de la mielina en la enfermedad de Alexander. Neurología. 2018;33:526–533.

Copyright © 2017. Sociedad Española de Neurología
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