Fig. 2

Mechanisms potentially underlying the beneficial effects of MSDC-0160. The drug’s action in Parkinson’s disease may include metabolic rewiring following inhibition of pyruvate uptake and downstream effects on mTOR and its associated pathways. We propose two hypotheses (mechanism A, left column and mechanism B, right column) to explain the observed effects of MSDC-0160. Mechanism A: (a) Activated mTORC1 inhibits insulin receptor substrate (IRS1) through a phosphorylation of serine residues. This inhibition of IRS1 results in dampened autophagy and enhanced inflammatory mechanisms; (b) Inhibition of mTORC1 (by MSDC-0160) may allow IRS1 signaling which may culminate in enhanced autophagy and cytoprotection. As an alternative mechanism (Mechanism B): (a) Activated mTORC1 is known to promote anabolic processes while inhibiting catabolic processes like autophagy; (b) Conceivably, MSDC-0160 treatment may also inhibit mTORC1 through AMPK activity, which could promote autophagic mechanisms while also minimizing inflammation