Apoptosis signal-regulating kinase 1 modulates the phenotype of α-synuclein transgenic mice

alpha-Synuclein is a key pathogenic protein in alpha-synucleinopathies including Parkinson's disease, and its overexpression and aggregation in model systems are associated with a neuroinflammatory response and increased oxidative stress. Apoptosis signal-regulating kinase 1 (ASK1) is activated upon stress signaling events such as oxidative stress and is a central player linking oxidative stress with neuroinflammation. Here, we demonstrate that overexpression of human alpha-synuclein activates ASK1 in both PC12 cells and in the brains of alpha-synuclein transgenic mice. Deleting ASK1 in mice mitigates the neuronal damage and neuroinflammation induced by alpha-synuclein and improves performance of the animals on the rotarod. ASK1 deletion does not impact the aggregation profile or phosphorylation state of a-synuclein in the mouse brain. These results collectively implicate ASK1 in the cascade of events triggered by alpha-synuclein overexpression, likely because of the inflammatory response and oxidative stress that lead to ASK1 activation. These conclusions raise the possibility that potent antioxidants and anti-inflammatory agents may ameliorate the phenotype of alpha-synucleinopathies. (C) 2015 Elsevier Inc. All rights reserved.