Human Molecular Genetics Advance Access originally published online on February 14, 2008
Human Molecular Genetics 2008 17(11):1540-1555; doi:10.1093/hmg/ddn042
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Autophagy induced by Alexander disease-mutant GFAP accumulation is regulated by p38/MAPK and mTOR signaling pathways
1 Department of Pathology, Center for Neurobiology and Behavior 2 Department of Neurology, Center for Parkinson’s Disease and Other Movement Disorders, Columbia University, New York, NY 10032, USA 3 Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA 4 Waisman Center, University of Wisconsin, Madison, USA
* To whom correspondence should be addressed at: Department of Pathology, P&S Rm 15-420, Columbia University College of P&S, 630 W. 168th St., New York, NY 10032, USA. Tel: +1 2123053554; Fax: +1 2123054548; Email: jeg5{at}columbia.edu
Received September 21, 2007; Revised January 31, 2008; Accepted February 7, 2008
Glial fibrillary acidic protein (GFAP) is the principle intermediate filament (IF) protein in astrocytes. Mutations in the GFAP gene lead to Alexander disease (AxD), a rare, fatal neurological disorder characterized by the presence of abnormal astrocytes that contain GFAP protein aggregates, termed Rosenthal fibers (RFs), and the loss of myelin. All GFAP mutations cause the same histopathological defect, i.e. RFs, though little is known how the mutations affect protein accumulation as well as astrocyte function. In this study, we found that GFAP accumulation induces macroautophagy, a key clearance mechanism for prevention of aggregated proteins. This autophagic response is negatively regulated by mammalian target of rapamycin (mTOR). The activation of p38 MAPK by GFAP accumulation is in part responsible for the down-regulation of phosphorylated-mTOR and the subsequent activation of autophagy. Our study suggests that AxD mutant GFAP accumulation stimulates autophagy, in a manner regulated by p38 MAPK and mTOR signaling pathways. Autophagy, in turn, serves as a mechanism to reduce GFAP levels.
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