Alexander disease is a rare and typically fatal neurodegenerative disease of childhood that results from heterozygous mutations in the gene encoding the type III intermediate filament protein GFAP. The pathological signature of the disorder is the Rosenthal fiber, a cytoplasmic inclusion containing intermediate filaments and small heat shock proteins that accumulates in astrocytes throughout the CNS. Prior investigations by our group have let to the acceptance of GFAP mutations as the cause for nearly all cases of Alexander disease, and the rapid translation of this information to clinical practice as the standard for diagnosis. However, the mechanisms by which GFAP mutations cause astrocyte dysfunction and disease remain unclear. The goals of this Program Project are to develop novel model systems of human astrocytes, investigate the impact of mutant GFAP and GFAP excess in astrocytes on neuronal development, viability, and function, and study the pathways by which mis-folded proteins are cleared from the brain. In addition, we will identify and characterize genetic modifiers of disease phenotype and test potential strategies for treatment. Our studies span genetic, biochemical, cellular, physiological, and morphological approaches to these questions, and include model systems ranging from invertebrate through human. The Program will link four laboratories, one using human induced pluripotent stem cells, one using Drosophila, and two using mouse models. An administrative core will coordinate financial reporting, monitor IACUC approvals, and support communication between the groups as well as with the internal and external advisory committees. The Program will promote a focused effort on the role of GFAP in disease, by fostering sharing of reagents, animals, and results among the four labs, through cross-fertilization of ideas, and by regular communication and meetings among laboratory members. These studies promise novel insights into the consequences of GFAP toxicity and the role of astrocytes in brain function and disease. Our hope is that such studies will ultimately lea to strategies for mitigating the devastating effects of astrocyte dysfunction.

Public Health Relevance

We are studying the role in disease of astrocytes, one of the major cell types in the brain and spinal cord of all vertebrates. We are using the rare disorder, Alexander disease, as a model system in which to address these questions, and to explore novel ways of restoring astrocyte function when it is impaired.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
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Special Emphasis Panel (ZHD1-DSR-K (41))
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Parisi, Melissa
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University of Wisconsin Madison
Schools of Veterinary Medicine
United States
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Wang, Liqun; Xia, Jing; Li, Jonathan et al. (2018) Tissue and cellular rigidity and mechanosensitive signaling activation in Alexander disease. Nat Commun 9:1899
Jones, Jeffrey R; Kong, Linghai; Hanna 4th, Michael G et al. (2018) Mutations in GFAP Disrupt the Distribution and Function of Organelles in Human Astrocytes. Cell Rep 25:947-958.e4
Hagemann, Tracy L; Powers, Berit; Mazur, Curt et al. (2018) Antisense suppression of glial fibrillary acidic protein as a treatment for Alexander disease. Ann Neurol 83:27-39
Moody, Laura R; Barrett-Wilt, Gregory A; Sussman, Michael R et al. (2017) Glial fibrillary acidic protein exhibits altered turnover kinetics in a mouse model of Alexander disease. J Biol Chem 292:5814-5824
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Kjaerby, Celia; Rasmussen, Rune; Andersen, Mie et al. (2017) Does Global Astrocytic Calcium Signaling Participate in Awake Brain State Transitions and Neuronal Circuit Function? Neurochem Res 42:1810-1822
Lin, Ni-Hsuan; Huang, Yu-Shan; Opal, Puneet et al. (2016) The role of gigaxonin in the degradation of the glial-specific intermediate filament protein GFAP. Mol Biol Cell 27:3980-3990
Tao, Yunlong; Zhang, Su-Chun (2016) Neural Subtype Specification from Human Pluripotent Stem Cells. Cell Stem Cell 19:573-586
Lu, Jianfeng; Zhong, Xuefei; Liu, Huisheng et al. (2016) Generation of serotonin neurons from human pluripotent stem cells. Nat Biotechnol 34:89-94

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