Astrocyte-Specific Overexpression of Nrf2 Delays Motor Pathology and Synuclein Aggregation throughout the CNS in the Alpha-Synuclein Mutant (A53T) Mouse Model

• Published in: The Journal of neuroscience Vol. 32; no. 49; pp. 17775 - 17787
• Main Authors: Gan, Li, Vargas, Marcelo R., Johnson, Delinda A., Johnson, Jeffrey A.
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 05.12.2012
• Subjects: alpha-Synuclein - genetics; alpha-Synuclein - metabolism; Animals; Antioxidant Response Elements - genetics; Astrocytes - metabolism; Autophagy - genetics; Cell Survival - genetics; Cell Survival - physiology; Central Nervous System - metabolism; Central Nervous System - pathology; Central Nervous System - ultrastructure; Disease Models, Animal; Female; Gliosis - genetics; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Motor Neurons - pathology; Neuroprotective Agents - metabolism; NF-E2-Related Factor 2 - biosynthesis; NF-E2-Related Factor 2 - genetics; Oxidative Stress - genetics; Parkinson Disease - metabolism; Parkinson Disease - pathology; Phosphorylation
• ISSN: 0270-6474; 1529-2401; 1529-2401
• DOI: 10.1523/JNEUROSCI.3049-12.2012

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.