S‐Glutathionylation of Keap1: a new role for glutathione S‐transferase pi in neuronal protection

Oxidative stress is a key pathological feature of Parkinson's disease (PD). Glutathione S ‐transferase pi (GSTP) is a neuroprotective antioxidant enzyme regulated at the transcriptional level by the antioxidant master regulator nuclear factor‐erythroid 2‐related factor 2 (Nrf2). Here, we show for the first time that upon MPTP‐induced oxidative stress, GSTP potentiates S ‐glutathionylation of Kelch‐like ECH‐associated protein 1 (Keap1), an endogenous repressor of Nrf2, in vivo . S ‐glutathionylation of Keap1 leads to Nrf2 activation and subsequently increases expression of GSTP. This positive feedback regulatory loop represents a novel mechanism by which GSTP elicits antioxidant protection in the brain.