Niemann-Pick Type C Disease Reveals a Link between Lysosomal Cholesterol and PtdIns(4,5)P2 That Regulates Neuronal Excitability

• DOI: 10.1016/j.celrep.2019.04.099
• Publication Date: 2019-05-28T14:32:07Z
• Authors: Oscar Vivas; Scott A. Tiscione; Rose E. Dixon; Daniel S. Ory; Eamonn J. Dickson
• Keywords: Male; Phosphatidylinositol 4,5-Diphosphate; 0301 basic medicine; 5)P(2); Medical Physiology; ABCA1; Neurodegenerative; Inbred C57BL; Type C; Mice; 2.1 Biological and endogenous factors; Biology (General); Mice, Knockout; Neurons; 0303 health sciences; neurodegeneration; Intracellular Signaling Peptides and Proteins; Niemann-Pick Disease, Type C; phosphoinositides; Biological Sciences; 3. Good health; Phosphatidylinositol 4; Biological sciences; Cholesterol; KCNQ2/3 channels; Neurological; 5-Diphosphate; Female; ATP Binding Cassette Transporter 1; QH301-705.5; 1.1 Normal biological development and functioning; Knockout; 610; Nerve Tissue Proteins; 612; Article; KCNQ3 Potassium Channel; 03 medical and health sciences; Niemann-Pick C1 Protein; Niemann-Pick Disease; excitability; Animals; KCNQ2 Potassium Channel; PtdIns(4; Cell Membrane; Neurosciences; cholesterol; Biological Transport; NPC1; Mice, Inbred C57BL; NPC1 disease; Biochemistry and Cell Biology; Lysosomes

There is increasing evidence that the lysosome is involved in the pathogenesis of a variety of neurodegenerative disorders. Thus, mechanisms that link lysosome dysfunction to the disruption of neuronal homeostasis offer opportunities to understand the molecular underpinnings of neurodegeneration and potentially identify specific therapeutic targets. Here, using a monogenic neurodegenerative disorder, NPC1 disease, we demonstrate that reduced cholesterol efflux from lysosomes aberrantly modifies neuronal firing patterns. The molecular mechanism linking alterations in lysosomal cholesterol egress to intrinsic tuning of neuronal excitability is a transcriptionally mediated upregulation of the ABCA1 transporter, whose PtdIns(4,5)P2-floppase activity decreases plasma membrane PtdIns(4,5)P2. The consequence of reduced PtdIns(4,5)P2 is a parallel decrease in a key regulator of neuronal excitability, the voltage-gated KCNQ2/3 potassium channel, which leads to hyperexcitability in NPC1 disease neurons. Thus, cholesterol efflux from lysosomes regulates PtdIns(4,5)P2 to shape the electrical and functional identity of the plasma membrane of neurons in health and disease.