Impaired striatal glutathione metabolism induces dopamine increase and motor dysfunction.

Abstract

Identification of initial triggering events in neurodegenerative disorders is critical to the development of preventive therapies. In Huntington’s disease (HD), hyperdopaminergia triggered by dysfunction of inhibitory indirect pathway spiny projection neurons (iSPNs) is believed to induce hyperkinesia, an early-stage HD symptom. Loss of TrkB signalling in iSPNs results in spontaneous motor dysfunction consistent with early HD hyperkinesia. We now show that this is preceded by striatal hyperdopaminergia at the pre-symptomatic stage induced by an increase in midbrain dopaminergic neurons. iSPNs transcriptome analysis revealed de-regulation of metabolic pathways in the absence of TrkB signalling, including up-regulation of Gsto2, encoding the glutathione S-transferase omega-2 (GSTO2). Selective in vivo knockdown of Gsto2 in iSPNs was sufficient to prevent dopaminergic dysfunction and block the onset of HD-like motor symptoms, identifying a functional link between iSPN dysfunction and striatal hyperdopaminergia and a putative disease-modifying enzyme that may be targeted in early stages of HD.