The DOI matches its Crossref record; 11 of the 11 references it cites were found in a registry or an index.
Autophagy induced by Alexander disease-mutant GFAP accumulation is regulated by p38/MAPK and mTOR signaling pathways
Open accessAbstract
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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Cites
LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing.
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Self-citation
Cited by
Regulation of Mammalian Autophagy in Physiology and Pathophysiology
Ravikumar, B., Sarkar, S., Davies, J. E., Futter, M., Garcia-Arencibia, M., Green-Thompson, Z. W., Jimenez-Sanchez, M., Korolchuk, V. I., Lichtenberg, M., Luo, S., et al. (2010) · Physiological Reviews · doi:10.1152/physrev.00030.2009 · Cited by 1,727
Myelin in the Central Nervous System: Structure, Function, and Pathology
Stadelmann, C., Timmler, S., Barrantes-Freer, A., & Simons, M. (2019) · Physiological Reviews · doi:10.1152/physrev.00031.2018 · Cited by 728
CD14 and Toll-Like Receptors 2 and 4 Are Required for Fibrillar Aβ-Stimulated Microglial Activation
Reed-Geaghan, E. G., Savage, J. C., Hise, A. G., & Landreth, G. E. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.3158-09.2009 · Cited by 591
Wang, N., Feng, Y., Zhu, M., Tsang, C., Man, K., Tong, Y., & Tsao, S. (2010) · Journal of Cellular Biochemistry · doi:10.1002/jcb.22869 · Cited by 289
Deciphering the astrocyte reaction in Alzheimer's disease
Perez-Nievas, B. G., & Serrano-Pozo, A. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00114 · Cited by 282
Metadata
- Authors
- Tang, G., Yue, Z., Talloczy, Z., Hagemann, T., Cho, W., Messing, A., Sulzer, D. L., & Goldman, J. E.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2008-02-07
- Volume
- 17
- Issue
- 11
- Pages
- 1540-1555
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2129962143
- Cited by
- 172
- References
- 11
- FWCI
- 7.23
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Tang, G., Yue, Z., Talloczy, Z., Hagemann, T., Cho, W., Messing, A., Sulzer, D. L., & Goldman, J. E. (2008). Autophagy induced by Alexander disease-mutant GFAP accumulation is regulated by p38/MAPK and mTOR signaling pathways. Human Molecular Genetics. https://doi.org/10.1093/hmg/ddn042
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