Title: Lipid Trafficking, Dopamine Signaling, and Parkinson's Disease
Parkinson’s disease (PD) is associated with disruption of endolysosomal transport, leading to loss of dopamine (DA) neurons that manifests by coding defects in cortico-striatal-thalamic circuits. Amongst cell biological pathways associated with PD, lysosomal integral membrane protein-2 (LIMP-2/SCARB2) is a member of the scavenger receptor family that includes CD36 and SR-B1, and is an acid glucocerebrosidase (GCase) receptor implicated in Gaucher and Parkinson’s disease. Here, I describe a crystal structure of a LIMP-2 luminal domain dimer with bound lipids that defines a structural basis for a novel form of lipid trafficking with implications for trafficking dysfunction in PD. A therapeutic staple upon the death of DA neurons is dopamine replacement therapy using either the dopamine precursor L-DOPA or direct agonism of dopamine receptors. Amongst dopamine receptor subtypes, selective activation of dopamine D1 receptors (D1Rs) has been pursued for 40 years as a therapeutic strategy for diverse neurologic and psychiatric diseases due to the fundamental role in motor function, reward processing, and cognition. All known D1R-selective agonists are catechols, which are rapidly metabolized and desensitize the D1R after prolonged exposure, reducing agonist response. As such, drug-like selective D1R agonists have remained elusive. Here, I describe a novel series of selective, potent non-catechol D1R agonists with excellent drug-like properties and a distinct binding mode that significantly reduces receptor desensitization and recruitment of β-arrestin. An integrated understanding of cellular and signaling defects in PD holds promise for the development of novel therapeutics.