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: Ni-Hsuan Lin, Yu-Shan Huang, Puneet Opal, Robert D Goldman, Albee Messing, Ming-Der Perng
• Journal: Molecular biology of the cell (Mol Biol Cell) Vol. 27 Issue 25 Pg. 3980-3990 (12 15 2016) ISSN: 1939-4586 [Electronic] United States
• PMID: 27798231 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 Lin, Huang, et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

Chemical References

• Cytoskeletal Proteins
• GAN protein, human
• Glial Fibrillary Acidic Protein
• Proteasome Endopeptidase Complex

Topics

• Alexander Disease (metabolism)
• Astrocytes (metabolism, physiology)
• Cells, Cultured
• Cytoskeletal Proteins (genetics, metabolism)
• Giant Axonal Neuropathy (genetics, metabolism)
• Glial Fibrillary Acidic Protein (genetics, metabolism)
• Humans
• Mutation
• Proteasome Endopeptidase Complex (metabolism)
• Proteolysis