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The Significance of Deiminated GFAP in Neurodegenerative Diseases with Special Emphasis on Alexander Disease

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Protein Deimination in Human Health and Disease

Abstract

A primary impetus for interest in a role for deiminated proteins in neurodegenerative diseases has been suggested that deimination of myelin basic protein (MBP) is a primary step in the development of multiple sclerosis (MS) (reviewed in Chap. 19). In brief, it is proposed that an unknown precipitating event causes increased peptidylarginine deiminase (PAD) activity, leading to deimination of MBP. This in turn results in disruption of the myelin structure, increased susceptibility of MBP to proteolysis, and release of MBP peptides that precipitate the autoimmune response that results in clinical symptoms. It was surprising, therefore, that a survey of proteins deiminated in MS, as well as in other CNS disorders, suggested that glial fibrillary acidic protein (GFAP) is the more predominant target. This finding raises the possibility that deimination of GFAP could have a general role in neurodegenerative disorders. This chapter explores this premise, with special emphasis on Alexander disease (AxD) as a likely candidate for an effect, since this disease is caused by dominant mutations in the GFAP gene. We begin with a description of GFAP and AxD, and then review evidence that astrocytes are a major repository for PAD in the CNS, and finally that GFAP is a primary target of its activity in both normal conditions and in several neurodegenerative disorders. This is followed by a discussion of the possible physiological effects of GFAP deimination and how these might influence disease states.

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Abbreviations

AlzD:

Alzheimer’s disease

AxD:

Alexander disease

EAE:

Experimental autoimmune encephalomyelitis

GFAP:

Glial fibrillary acidic protein

IF:

Intermediate filament

KO:

Gene knockout

LC-MS/MS:

Liquid chromatography-tandem mass spectrometry

mass spec:

Mass spectroscopy

MBP:

Myelin basic protein

MS:

Multiple sclerosis

MW:

Molecular weight

PAD:

Peptidylarginine deiminase

rh:

Recombinant human

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Authors and Affiliations

  1. Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA

    Michael Brenner

  2. Department of Neurology, University of Alabama at Birmingham and The Birmingham Veterans Administration Medical Center, Birmingham, AL, USA

    Anthony P. Nicholas

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  1. Michael Brenner
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Correspondence to Michael Brenner .

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Editors and Affiliations

  1. Department of Neurology, University of Alabama at Birmingham and The Birmingham Veterans Administration Medical Center, Birmingham, Alabama, USA

    Anthony P. Nicholas

  2. Bascom Palmer Eye Institute, University of Miami, Miami, Florida, USA

    Sanjoy K. Bhattacharya

  3. Department of Biochemistry and Molecular Pharmacology, UMASS Medical School, Worcester, Massachusetts, USA

    Paul R. Thompson

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Brenner, M., Nicholas, A.P. (2017). The Significance of Deiminated GFAP in Neurodegenerative Diseases with Special Emphasis on Alexander Disease. In: Nicholas, A., Bhattacharya, S., Thompson, P. (eds) Protein Deimination in Human Health and Disease. Springer, Cham. https://doi.org/10.1007/978-3-319-58244-3_20

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