Studies of SLC41A1, a Mg2+-Transporting Protein Linked to Parkinson's Disease

Project Summary/Abstract Magnesium has been largely overlooked in neurobiology as a “housekeeping” ion, but this view is directly challenged by evidence which shows that mutations in Mg2+ transporting proteins are associated with neurodegeneration. Mutations in the Mg2+ transporting protein SLC41A1 are associated with both increased and decreased risk of Parkinson's disease (PD). SLC41A1 might therefore be a causative gene for PD. Despite this, little is known about SLC41A1. For example, we do not yet know if it causes rapid changes in free cytosolic Mg2+ (like an ion channel) or if it works to maintain the levels of free cytosolic Mg2+ within the range required for normal cellular function (like a transporter). This distinction is required both to define the role of SLC41A1 in the Mg2+ homeostasis and its role in PD pathogenesis. Furthermore, a cellular role for SLC41A1 has not been determined and it is therefore not known how its dysfunction might lead to PD. We hypothesize that SLC41A1 is a Mg2+-permeable ion channel which, through its role in maintaining the cellular Mg2+ homeostasis, helps maintain the mitochondrial membrane potential and ensures that ATP production via oxidative phosphorylation proceeds undisturbed. In this application for a Stephen I. Katz ESI grant, we propose to use liposomal flux assays and lipid bilayer studies as well as electron cryo-microscopy (cryo-EM) to determine how SLC41A1 mediates Mg2+ transport, and to generate a model to determine its cellular role. Neuronal Mg2+ transport has thus far been virtually untouched by biophysical and structural investigation and the study proposed here represents the first steps towards understanding the molecular mechanisms of neuronal Mg2+ homeostasis as well as the Mg2+-dependent molecular origins of neurodegenerative disorders. In the long term, this study of SLC41A1 has the potential to lead to novel treatments of and preventative strategies against PD, a debilitating disease which costs the US health system more than $14 billion each year.