LAUSR

Mitochondrial pyruvate carrier (MPC) is a key protein complex in the control of cellular metabolism. Recent evidence suggests that a group of antidiabetic compounds, called thiazolidinedione (TZD) insulin sensitizers, slow the entry of pyruvate into mitochondria through MPC. In parallel, TZDs activate the transcription factor, peroxisome proliferatoractivated receptor-g (PPARg). However, because of the adverse effects associated with PPARg activation (fluid retention, weight gain, and increased risk of bladder cancer), the use of TZDs in diabetes has declined in recent years. Nevertheless, it has gained importance in research through its protective role in Parkinson’s disease (PD): In diabetic patients prescribed with TZDs, the risk of developing PD decreases up to 29%. In addition, recent research has shown that both diabetes and PD have common pathophysiological mechanisms, such as mitochondrial and autophagic dysfunction and inflammation; therefore, MPC regulation could restore altered molecular pathways during PD. Ghosh and colleagues use MSDC-0160, a compound that reduces MPC activity without activating PPARg, to evaluate its neuroprotective and anti-inflammatory role in different models of PD. These investigators demonstrate that MSDC-0160 shields cultured nematode, mouse, and human dopaminergic neurons against cytotoxic stimuli from MPP. Protection by this compound is also observed in a genetic (heterozygous mice for Engrailed1, En1) and a pharmacological model (MPTP injection). Oral administration of MSDC-0160 rescues the loss of dopaminergic neurons of the SN, as well as the decrease in dopamine and DOPAC induced in these models. Furthermore, treated mice display a locomotor improving in open-field and rotarod tests. The investigators then study the molecular mechanism underlying MSDC-0160 treatment. They show that modulation of MPC has prompt effects on mitochondrial function, normalizing oxygen consumption in several parkinsonian models. Moreover, the investigators demonstrate that the mammalian target of rapamycin (mTOR) pathway is necessary for the neuroprotective effect of MSDC-0160. In this way, they suggest that MPC modulation induces autophagy as a part of the long-term response that prevents neurodegeneration. In addition, they show that MSDC-0160 is involved in neuroinflammation, reducing the high astrogliosis and microgliosis observed in different models of PD. Ghosh and colleagues provide many evidences that make MPC a powerful therapeutic target in PD thanks to its neuroprotective role demonstrated in several models of PD. Regulating MPC is an exciting strategy that should be addressed with compounds such as MSDC-0160, a treatment that acts toward enhancing the survival of dopaminergic neurons and reducing microglia activation, lacking the negative side effects of PPARg activation.