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BMC Neurology
Published in: BMC Neurology 1/2017

Open Access 01-12-2017 | Research article

Aggregation-prone GFAP mutation in Alexander disease validated using a zebrafish model

Authors: So-Hyun Lee, Tai-Seung Nam, Kun-Hee Kim, Jin Hee Kim, Woong Yoon, Suk-Hee Heo, Min Jung Kim, Boo Ahn Shin, Ming-Der Perng, Hyon E. Choy, Jihoon Jo, Myeong-Kyu Kim, Seok-Yong Choi

Published in: BMC Neurology | Issue 1/2017

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Abstract

Background

Alexander disease (AxD) is an astrogliopathy that predominantly affects the white matter of the central nervous system (CNS), and is caused by a mutation in the gene encoding the glial fibrillary acidic protein (GFAP), an intermediate filament primarily expressed in astrocytes and ependymal cells. The main pathologic feature of AxD is the presence of Rosenthal fibers (RFs), homogeneous eosinophilic inclusions found in astrocytes. Because of difficulties in procuring patient’ CNS tissues and the presence of RFs in other pathologic conditions, there is a need to develop an in vivo assay that can determine whether a mutation in the GFAP results in aggregation and is thus disease-causing.

Methods

We found a GFAP mutation (c.382G > A, p.Asp128Asn) in a 68-year-old man with slowly progressive gait disturbance with tendency to fall. The patient was tentatively diagnosed with AxD based on clinical and radiological findings. To develop a vertebrate model to assess the aggregation tendency of GFAP, we expressed several previously reported mutant GFAPs and p.Asp128Asn GFAP in zebrafish embryos.

Results

The most common GFAP mutations in AxD, p.Arg79Cys, p.Arg79His, p.Arg239Cys and p.Arg239His, and p.Asp128Asn induced a significantly higher number of GFAP aggregates in zebrafish embryos than wild-type GFAP.

Conclusions

The p.Asp128Asn GFAP mutation is likely to be a disease-causing mutation. Although it needs to be tested more extensively in larger case series, the zebrafish assay system presented here would help clinicians determine whether GFAP mutations identified in putative AxD patients are disease-causing.
Literature
1.
2.
Heaven MR, Flint D, Randall SM, Sosunov AA, Wilson L, Barnes S, Goldman JE, Muddiman DC, Brenner M. Composition of Rosenthal fibers, the protein aggregate Hallmark of Alexander disease. J Proteome Res. 2016;15(7):2265–82.CrossRefPubMedPubMedCentral
3.
Johnson AB, Brenner M. Alexander's disease: clinical, pathologic, and genetic features. J Child Neurol. 2003;18(9):625–32.CrossRefPubMed
4.
5.
Sawaishi Y. Review of Alexander disease: beyond the classical concept of leukodystrophy. Brain and Development. 2009;31(7):493–8.CrossRefPubMed
6.
Alexander WSProgressive fibrinoid degeneration of fibrillary astrocytes associated with mental retardation in a hydrocephalic infant. Brain 1949, 72(3):373–381, 373 pl.
7.
Rosenthal W. Über eine eigenthümliche, mit Syringomyelie complicirte Geschwulst des Rückenmarks. Bietr Pathol Anat. 1898;23:111–43.
8.
Brenner M, Johnson AB, Boespflug-Tanguy O, Rodriguez D, Goldman JE, Messing A. Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease. Nat Genet. 2001;27(1):117–20.CrossRefPubMed
9.
10.
Mignot C, Boespflug-Tanguy O, Gelot A, Dautigny A, Pham-Dinh D, Rodriguez D. Alexander disease: putative mechanisms of an astrocytic encephalopathy. Cell Mol Life Sci. 2004;61(3):369–85.CrossRefPubMed
11.
Prust M, Wang J, Morizono H, Messing A, Brenner M, Gordon E, Hartka T, Sokohl A, Schiffmann R, Gordish-Dressman H, et al. GFAP mutations, age at onset, and clinical subtypes in Alexander disease. Neurology. 2011;77(13):1287–94.CrossRefPubMedPubMedCentral
12.
Balbi P, Seri M, Ceccherini I, Uggetti C, Casale R, Fundaro C, Caroli F, Santoro L. Adult-onset Alexander disease: report on a family. J Neurol. 2008;255(1):24–30.CrossRefPubMed
13.
Li R, Johnson AB, Salomons G, Goldman JE, Naidu S, Quinlan R, Cree B, Ruyle SZ, Banwell B, D'Hooghe M, et al. Glial fibrillary acidic protein mutations in infantile, juvenile, and adult forms of Alexander disease. Ann Neurol. 2005;57(3):310–26.CrossRefPubMed
14.
Schmidt S, Wattjes MP, Gerding WM, van der Knaap M. Late onset Alexander's disease presenting as cerebellar ataxia associated with a novel mutation in the GFAP gene. J Neurol. 2011;258(5):938–40.CrossRefPubMed
15.
Wippold FJ 2nd, Perry A, Lennerz J. Neuropathology for the neuroradiologist: Rosenthal fibers. AJNR Am J Neuroradiol. 2006;27(5):958–61.PubMed
16.
Bachetti T, Caroli F, Bocca P, Prigione I, Balbi P, Biancheri R, Filocamo M, Mariotti C, Pareyson D, Ravazzolo R, et al. Mild functional effects of a novel GFAP mutant allele identified in a familial case of adult-onset Alexander disease. Eur J Hum Genet. 2008;16(4):462–70.CrossRefPubMed
17.
Boczek NJ, Sigafoos AN, Zimmermann MT, Maus RL, Cousin MA, Blackburn PR, Urrutia R, Clark KJ, Patterson MC, Wick MJ, et al. Functional characterization of a GFAP variant of uncertain significance in an Alexander disease case within the setting of an individualized medicine clinic. Clin Case Rep. 2016;4(9):885–95.CrossRefPubMedPubMedCentral
18.
Der Perng M, Su M, Wen SF, Li R, Gibbon T, Prescott AR, Brenner M, Quinlan RA. 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. 2006;79(2):197–213.CrossRefPubMedCentral
19.
Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science. 1996;274(5284):99–102.CrossRefPubMed
20.
Nam TS, Kim JH, Chang CH, Yoon W, Jung YS, Kang SY, Shin BA, Perng MD, Choi SY, Kim MK. Identification of a novel nonsense mutation in the rod domain of GFAP that is associated with Alexander disease. Eur J Hum Genet. 2015;23(1):72–8.CrossRefPubMed
21.
Grunwald DJ, Eisen JS. Headwaters of the zebrafish -- emergence of a new model vertebrate. Nat Rev Genet. 2002;3(9):717–24.CrossRefPubMed
22.
23.
Kawai H, Arata N, Nakayasu H. Three-dimensional distribution of astrocytes in zebrafish spinal cord. Glia. 2001;36(3):406–13.CrossRefPubMed
24.
Nielsen AL, Jorgensen AL. Structural and functional characterization of the zebrafish gene for glial fibrillary acidic protein, GFAP. Gene. 2003;310:123–32.CrossRefPubMed
25.
26.
27.
Kim JH, Lee SR, Li LH, Park HJ, Park JH, Lee KY, Kim MK, Shin BA, Choi SY. High cleavage efficiency of a 2A peptide derived from porcine teschovirus-1 in human cell lines, zebrafish and mice. PLoS One. 2011;6(4):e18556.CrossRefPubMedPubMedCentral
28.
Urasaki A, Morvan G, Kawakami K. Functional dissection of the Tol2 transposable element identified the minimal cis-sequence and a highly repetitive sequence in the subterminal region essential for transposition. Genetics. 2006;174(2):639–49.CrossRefPubMedPubMedCentral
29.
Westerfield M: THE ZEBRAFISH BOOK: a guide for the laboratory use of zebrafish (Danio rerio), 5 edn: University of Oregon Press; 2007.
30.
Kimmel CB, Ballard WW, Kimmel SR, Ullmann B, Schilling TF. Stages of embryonic development of the zebrafish. Developmental dynamics : an official publication of the American Association of Anatomists. 1995;203(3):253–310.CrossRef
31.
Delongchamp RR, Razzaghi M, Lee T. Estimating false discovery rate and false non-discovery rate using the empirical cumulative distribution function of p-values in 'omics' studies. Genes Genom. 2011;33(5):461–6.CrossRef
32.
Chang KE, Pratt D, Mishra BB, Edwards N, Hallett M, Ray-Chaudhury A. Type II (adult onset) Alexander disease in a paraplegic male with a rare D128N mutation in the GFAP gene. Clin Neuropathol. 2015;34(5):298–302.CrossRefPubMedPubMedCentral
33.
Pareyson D, Fancellu R, Mariotti C, Romano S, Salmaggi A, Carella F, Girotti F, Gattellaro G, Carriero MR, Farina L, et al. Adult-onset Alexander disease: a series of eleven unrelated cases with review of the literature. Brain. 2008;131(Pt 9):2321–31.CrossRefPubMed
34.
Messing A, Head MW, Galles K, Galbreath EJ, Goldman JE, Brenner M. Fatal encephalopathy with astrocyte inclusions in GFAP transgenic mice. Am J Pathol. 1998;152(2):391–8.PubMedPubMedCentral
35.
Tang G, Yue Z, Talloczy Z, Hagemann T, Cho W, Messing A, Sulzer DL, Goldman JE. Autophagy induced by Alexander disease-mutant GFAP accumulation is regulated by p38/MAPK and mTOR signaling pathways. Hum Mol Genet. 2008;17(11):1540–55.CrossRefPubMedPubMedCentral
36.
Ebrahimi-Fakhari D, Wahlster L, Hoffmann GF, Kolker S. Emerging role of autophagy in pediatric neurodegenerative and neurometabolic diseases. Pediatr Res. 2014;75(1–2):217–26.CrossRefPubMed
37.
Faber PW, Alter JR, MacDonald ME, Hart AC. Polyglutamine-mediated dysfunction and apoptotic death of a Caenorhabditis Elegans sensory neuron. Proc Natl Acad Sci U S A. 1999;96(1):179–84.CrossRefPubMedPubMedCentral
38.
Iijima K, Liu HP, Chiang AS, Hearn SA, Konsolaki M, Zhong Y. Dissecting the pathological effects of human Abeta40 and Abeta42 in drosophila: a potential model for Alzheimer's disease. Proc Natl Acad Sci U S A. 2004;101(17):6623–8.CrossRefPubMedPubMedCentral
39.
Biswas P, Chavali VR, Agnello G, Stone E, Chakarova C, Duncan JL, Kannabiran C, Homsher M, Bhattacharya SS, Naeem MA, et al. A missense mutation in ASRGL1 is involved in causing autosomal recessive retinal degeneration. Hum Mol Genet. 2016;
40.
Gama Sosa MA, De Gasperi R, Elder GA. Modeling human neurodegenerative diseases in transgenic systems. Hum Genet. 2012;131(4):535–63.CrossRefPubMed
41.
Schiffer NW, Broadley SA, Hirschberger T, Tavan P, Kretzschmar HA, Giese A, Haass C, Hartl FU, Schmid B. Identification of anti-prion compounds as efficient inhibitors of polyglutamine protein aggregation in a zebrafish model. J Biol Chem. 2007;282(12):9195–203.CrossRefPubMed
42.
Chen YS, Lim SC, Chen MH, Quinlan RA, Perng MD. Alexander disease causing mutations in the C-terminal domain of GFAP are deleterious both to assembly and network formation with the potential to both activate caspase 3 and decrease cell viability. Exp Cell Res. 2011;317(16):2252–66.CrossRefPubMedPubMedCentral
43.
Jany PL, Hagemann TL, Messing A. GFAP expression as an indicator of disease severity in mouse models of Alexander disease. ASN Neuro. 2013;5(1):e00109.PubMedPubMedCentral
44.
Bennett RL, French KS, Resta RG, Doyle DL. Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of genetic counselors. J Genet Couns. 2008;17(5):424–33.CrossRefPubMed
Metadata
Title
Aggregation-prone GFAP mutation in Alexander disease validated using a zebrafish model
Authors
So-Hyun Lee
Tai-Seung Nam
Kun-Hee Kim
Jin Hee Kim
Woong Yoon
Suk-Hee Heo
Min Jung Kim
Boo Ahn Shin
Ming-Der Perng
Hyon E. Choy
Jihoon Jo
Myeong-Kyu Kim
Seok-Yong Choi
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Neurology / Issue 1/2017
Electronic ISSN: 1471-2377
DOI
https://doi.org/10.1186/s12883-017-0938-7

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