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

• DOI: 10.1523/jneurosci.3049-12.2012
• Publication Date: 2012-12-05T17:46:54Z
• Authors: Li Gan; Marcelo R. Vargas; Delinda A. Johnson; Jeffrey A. Johnson
• Keywords: Synucleinopathies; Neurotoxicity; Gliosis; KEAP1

Alpha synuclein (SYN) is a central player in the pathogenesis of sporadic and familial Parkinson's disease (PD). SYN aggregation oxidative stress are associated enhance each other's toxicity. It unknown whether redox-sensitive transcription factor nuclear erythroid 2-related 2 (Nrf2) plays role against toxicity SYN. To examine this, mice selectively overexpressing Nrf2 astrocytes (GFAP-Nrf2) were crossed with expressing human mutant (hSYN A53T ) neurons. Increased astrocytic delayed onset extended life span hSYN mice. This correlated increased motor neuron survival, reduced stress, attenuated gliosis spinal cord, as well dramatic decrease total phosphorylated (Ser129) Triton-insoluble aggregates. Furthermore, chaperone-mediated autophagy macroautophagy dysfunction observed Our data suggest that provides neuroprotection -mediated by promoting degradation through autophagy-lysosome pathway vivo . Thus, activation potential target to develop therapeutic strategies for treating pathologic synucleinopathies including PD.