Dissecting the importance of cholesterol homeostasis for neuronal function

Proper brain function requires robust mechanisms for maintaining a precise composition of lipids within neuronal plasma membranes (PMs). This is because PM lipids play major roles in neurotransmission and neuronal survival. In particular, dysregulation of cholesterol, a major class of structural and signaling lipids enriched in the PM, has been linked to neurodegenerative disorders, including the Alzheimer's disease. Despite decades of research into cholesterol metabolism, we still do not know how cells maintain appropriate levels of PM cholesterol. Cells either acquire cholesterol from external sources or produce it in the endoplasmic reticulum (ER). Thus, cells must keep track of how much cholesterol is in their PM, and make adjustments to cholesterol uptake and/or production to maintain appropriate levels. In our recent studies, we found that a new family of evolutionarily conserved and ER-anchored lipid transfer proteins, the GRAMD1s, detect the amount of cholesterol available in the PM and transport excessive PM cholesterol to the ER at sites of contact between these cellular structures (ER-PM contacts). GRAMD1s therefore allow the ER to sense the amount of PM cholesterol and adjust its production. GRAMD1s are expressed at high levels in the brain. Strikingly, recent human genetic studies have identified links between one of these proteins, GRAMD1b, and both intellectual disability and schizophrenia. Building on these exciting findings, we are currently 1) investigating the role of GRAMD1s in brain function and characterizing how a GRAMD1 mutation linked to intellectual disability affects GRAMD1 function, and 2) performing a CRISPR-based screen to identify other cholesterol transport systems that regulate cholesterol homeostasis. Our study will not only deepen our understanding of the fundamental mechanisms of cellular lipid distribution, but may lead to new therapeutic strategies for counteracting defects in cholesterol metabolism often seen in disease states.