title: The role of gigaxonin in the degradation of the glial-specific intermediate filament protein GFAP.
abstract: Alexander disease (AxD) is a primary genetic disorder of astrocytes caused by dominant mutations in the gene encoding the intermediate filament (IF) protein GFAP. This disease is characterized by excessive accumulation of GFAP, known as Rosenthal fibers, within astrocytes. Abnormal GFAP aggregation also occurs in giant axon neuropathy (GAN), which is caused by recessive mutations in the gene encoding gigaxonin. Given that one of the functions of gigaxonin is to facilitate proteasomal degradation of several IF proteins, we sought to determine whether gigaxonin is involved in the degradation of GFAP. Using a lentiviral transduction system, we demonstrated that gigaxonin levels influence the degradation of GFAP in primary astrocytes and in cell lines that express this IF protein. Gigaxonin was similarly involved in the degradation of some but not all AxD-associated GFAP mutants. In addition, gigaxonin directly bound to GFAP, and inhibition of proteasome reversed the clearance of GFAP in cells achieved by overexpressing gigaxonin. These studies identify gigaxonin as an important factor that targets GFAP for degradation through the proteasome pathway. Our findings provide a critical foundation for future studies aimed at reducing or reversing pathological accumulation of GFAP as a potential therapeutic strategy for AxD and related diseases.
authors: Institute of Molecular Medicine, College of Life Sciences, National Tsing Hua University, Hsinchu 300, Taiwan.
authors: Ni-Hsuan
authors: NH
authors: Lin
authors: Institute of Molecular Medicine, College of Life Sciences, National Tsing Hua University, Hsinchu 300, Taiwan.
authors: Yu-Shan
authors: YS
authors: Huang
authors: Davee Department of Neurology, Northwestern University, Chicago, IL 60611.|Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
authors: Puneet
authors: P
authors: Opal
authors: Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
authors: Robert D
authors: RD
authors: Goldman
authors: Waisman Center, University of Wisconsin-Madison, Madison, WI 53705.|Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI 53705.
authors: Albee
authors: A
authors: Messing
authors: Institute of Molecular Medicine, College of Life Sciences, National Tsing Hua University, Hsinchu 300, Taiwan mdperng@life.nthu.edu.tw.
authors: Ming-Der
authors: MD
authors: Perng
mesh_terms: D038261:Alexander Disease / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism / Q000502:physiology; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D056768:Giant Axonal Neuropathy / Q000235:genetics / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis
chemical_list: D003598:Cytoskeletal Proteins; C416508:GAN protein, human; D005904:Glial Fibrillary Acidic Protein; D046988:Proteasome Endopeptidase Complex