Alexander disease (AxD) patients carry heterozygous mutations within the coding region of GFAP. To facilitate mechanistic studies on the pathogenesis of AxD, and provide animal models suitable for testing potential therapies, our long-term goal has been to generate mouse models for this disorder. During the previous grant period we generated knock-in lines of mice carrying the most common GFAP mutations found in human AxD (equivalent to R79H, R239H, R239C, and R416W), and found that expression of the mutant GFAPs induces Rosenthal fibers (the hallmark pathologic feature), but the mice are viable. However, expressing the mutant GFAPs in the context of appropriate genetic modifiers (such as elevatingj/vild type GFAP) results in a lethal phenotype. In addition, altering GFAP expression either by simple over-expression or production of mutant GFAPs leads to induction of multiple stress pathways (aB-crystallin, Nrf2) that suggest specific hypotheses about pathogenesis and, ultimately, strategies for therapy. With the goals of understanding more precisely the consequences of abnormal GFAP expression in astrocytes, and of generating mouse models that reflect key phenotypic features of AxD in humans, we propose the following specific aims:
In Aim 1 we will test the consequences of expressing mutant GFAP protein and/or GFAP over-expression, for comparison with known features of the Alexander phenotype in humans. These studies will include both in vitro models using primary cultures of mouse astrocytes, as well as the in vivo knockin models carrying point mutations in the endogenous mouse GFAP gene. A range of properties will be examined, including biochemical, functional, and behavioral. Reversibility will also be assessed.
In Aim 2 we will test the role of the small stress protein aB-crystallin, as a modifier, by crossing the GFAP mice with knockouts of aB-crystallin or with newly generated transgenics that over-express aB-crystallin. Specific mechanisms by which excess aB-crystallin might achieve rescue will be evaluated. These studies promise novel information on the pathological significance of mutant intermediate filament expression in astrocytes, will suggest mechanisms by which primary astrocyte dysfunction leads to generalized CMS disease, and will identify critical stress pathways that could ultimately serve as the basis for therapies to mitigate the devastating effects of this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS042803-09
Application #
8284386
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
9
Fiscal Year
2011
Total Cost
$695,885
Indirect Cost
Name
University of Wisconsin Madison
Department
Type
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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Sosunov, Alexander A; McKhann 2nd, Guy M; Goldman, James E (2017) The origin of Rosenthal fibers and their contributions to astrocyte pathology in Alexander disease. Acta Neuropathol Commun 5:27
Wang, Liqun; Hagemann, Tracy L; Messing, Albee et al. (2016) An In Vivo Pharmacological Screen Identifies Cholinergic Signaling as a Therapeutic Target in Glial-Based Nervous System Disease. J Neurosci 36:1445-55
Heaven, Michael R; Flint, Daniel; Randall, Shan M et al. (2016) Composition of Rosenthal Fibers, the Protein Aggregate Hallmark of Alexander Disease. J Proteome Res 15:2265-82
Sosunov, Alexander A; McGovern, Robert A; Mikell, Charles B et al. (2015) Epileptogenic but MRI-normal perituberal tissue in Tuberous Sclerosis Complex contains tuber-specific abnormalities. Acta Neuropathol Commun 3:17
Wang, Liqun; Hagemann, Tracy L; Kalwa, Hermann et al. (2015) Nitric oxide mediates glial-induced neurodegeneration in Alexander disease. Nat Commun 6:8966
LaPash Daniels, Christine M; Paffenroth, Elizabeth; Austin, Elizabeth V et al. (2015) Lithium Decreases Glial Fibrillary Acidic Protein in a Mouse Model of Alexander Disease. PLoS One 10:e0138132
Minkel, Heather R; Anwer, Tooba Z; Arps, Kara M et al. (2015) Elevated GFAP induces astrocyte dysfunction in caudal brain regions: A potential mechanism for hindbrain involved symptoms in type II Alexander disease. Glia 63:2285-97
Olabarria, Markel; Putilina, Maria; Riemer, Ellen C et al. (2015) Astrocyte pathology in Alexander disease causes a marked inflammatory environment. Acta Neuropathol 130:469-86
Jany, Paige L; Agosta, Guillermo E; Benko, William S et al. (2015) CSF and Blood Levels of GFAP in Alexander Disease(1,2,3). eNeuro 2:

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