The DOI matches its Crossref record; 11 of the 11 references it cites were found in a registry or an index.
Astrocyte-Specific Overexpression of Nrf2 Delays Motor Pathology and Synuclein Aggregation throughout the CNS in the Alpha-Synuclein Mutant (A53T) Mouse Model
Open accessAbstract
Alpha synuclein (SYN) is a central player in the pathogenesis of sporadic and familial Parkinson's disease (PD). SYN aggregation and oxidative stress are associated and enhance each other's toxicity. It is unknown whether the redox-sensitive transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) plays a role against the toxicity of SYN. To examine this, mice selectively overexpressing Nrf2 in astrocytes (GFAP-Nrf2) were crossed with mice selectively expressing human mutant SYN (hSYN A53T ) in neurons. Increased astrocytic Nrf2 delayed the onset and extended the life span of the hSYN A53T mice. This correlated with increased motor neuron survival, reduced oxidative stress, and attenuated gliosis in the spinal cord, as well as a dramatic decrease in total hSYN A53T and phosphorylated (Ser129) hSYN A53T in Triton-insoluble aggregates. Furthermore, Nrf2 in astrocytes delayed chaperone-mediated autophagy and macroautophagy dysfunction observed in the hSYN A53T mice. Our data suggest that Nrf2 in astrocytes provides neuroprotection against hSYN A53T -mediated toxicity by promoting the degradation of hSYN A53T through the autophagy-lysosome pathway in vivo . Thus, activation of the Nrf2 pathway in astrocytes is a potential target to develop therapeutic strategies for treating pathologic synucleinopathies including PD.
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Cites
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Guidelines for the use and interpretation of assays for monitoring autophagy
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Self-citationAlaSOPro mutation in the gene encoding α-synuclein in Parkinson's disease
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Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes
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Impaired Degradation of Mutant α-Synuclein by Chaperone-Mediated Autophagy
Cuervo, A. M., Stefanis, L., Fredenburg, R., Lansbury, P. T., & Sulzer, D. (2004) · Science · doi:10.1126/science.1101738 · Cited by 2,024 · cited 1×
“SYN mutants actually bind to Lamp2a with higher affinity blocking their own degradation as well as other CMA substrates (Cuervo et al., 2004).”
Backgroundα-Synuclein impairs macroautophagy: implications for Parkinson’s disease
Winslow, A. R., Chen, C.-W., Corrochano, S., Acevedo-Arozena, A., Gordon, D. E., Peden, A. A., Lichtenberg, M., Menzies, F. M., Ravikumar, B., Imarisio, S., et al. (2010) · Journal of Cell Biology · doi:10.1083/jcb.201003122 · Cited by 825 · cited 1×
“SYN can also be degraded through macroautophagy in neuronal cells in vitro (Vogiatzi et al., 2008) and overexpression of SYN impairs macroautophagy (Winslow et al., 2010).”
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Cited by
The coming of age of chaperone-mediated autophagy
Kaushik, S., & Cuervo, A. M. (2018) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-018-0001-6 · Cited by 1,407
Sivandzade, F., Prasad, S., Bhalerao, A., & Cucullo, L. (2019) · Redox Biology · doi:10.1016/j.redox.2018.11.017 · Cited by 639
Elusive roles for reactive astrocytes in neurodegenerative diseases
Ben Haim, L., Carrillo-de Sauvage, M.-A., Ceyzériat, K., & Escartin, C. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00278 · Cited by 453
ROS and Brain Diseases: The Good, the Bad, and the Ugly
Popa-Wagner, A., Mitran, S., Sivanesan, S., Chang, E., & Buga, A.-M. (2013) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2013/963520 · Cited by 427
Astrocytes in Neurodegenerative Disease: Table 1.
Phatnani, H., & Maniatis, T. (2015) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a020628 · Cited by 420
Metadata
- Authors
- Gan, L., Vargas, M. R., Johnson, D. A., & Johnson, J. A.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2012-12-05
- Volume
- 32
- Issue
- 49
- Pages
- 17775-17787
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- OpenAlex
- W2065746707
- Cited by
- 182
- References
- 11
- FWCI
- 4.67
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Gan, L., Vargas, M. R., Johnson, D. A., & Johnson, J. A. (2012). Astrocyte-Specific Overexpression of Nrf2 Delays Motor Pathology and Synuclein Aggregation throughout the CNS in the Alpha-Synuclein Mutant (A53T) Mouse Model. The Journal of Neuroscience. https://doi.org/10.1523/jneurosci.3049-12.2012
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