The long-term goal of this application is to gain information about mechanisms that control homeostasis of membrane lipids in cells of the nervous system. Such control is critical to ensure normal function and traffic of cellular membranes, and dysfunction of these mechanisms result in neurological and psychiatric diseases. The specific goal of this application is to advance knowledge of lipid transfer reactions that occur at contact sites between the endoplasmic reticulum (ER) and other membranes and that are mediated by membrane tethering proteins containing lipid transport modules of the TULIP domain superfamily. The occurrence of protein- dependent, but membrane traffic-independent, transport of lipids between the ER and other membranes has been known for decades. Recently, however, it has become clear that much of such transport occurs at membrane contact sites. Additionally, several new proteins that localize at membrane contact sites and contain lipid transport modules have been identified. These mechanisms so far have not been investigated in cells of the nervous system, although contacts between the ER and other organelles have been described in all neuronal compartments including synapses. Here I propose to investigate the properties, mechanisms of action and physiological functions of two proteins that function at contacts between the ER and other membranes. The first is TMEM24, an intrinsic ER protein by far preferentially expressed in neurons and neuroendocrine cells. TMEM24 contains a lipid transport module of the TULIP domain superfamily (an SMP domain) and functions as a regulated tether between the ER and the plasma membrane. We hypothesize that the lipid transport function of TMEM24 regulates signaling reactions at the plasma membrane. The second is Vps13A/chorein, a very large protein without transmembrane regions that we have found to be concentrated at ER-mitochondria contacts, where it tethers their membranes. Loss-of-function mutations in Vps13A result in chorea-acanthocytosis, a neurodegenerative condition resembling Huntington's disease with an associated defect of red blood cells. Mutations in a closely related protein, Vps13C, are responsible for a familial form of Parkinson's disease. Based on preliminary results we hypothesize that one function of Vps13A is to mediate lipid transport between the ER and mitochondria via SMP like domains. We will test these hypotheses with a variety of complementary experimental strategies ranging from in vitro reconstitution of lipid transport between artificial liposomes, to studies in cultured cells (including iPS cells) and mutant mice. Results of this research will provide insight into completely unknown aspects of neuronal and synaptic function and into pathogenetic mechanisms in neurodegenerative diseases.

Public Health Relevance

The goal of this proposal is to gain information about mechanisms that control the traffic of membrane lipids within cells of the nervous system and on the impact of dysfunction of these mechanisms in neurodegenerative conditions. I will investigate proteins that reside at membrane contact sites and transport lipids via lipid transfer modules of the TULIP domain superfamily. Specifically, I will focus on the function of TMEM24, a Ca2+ regulated protein that tethers the endoplasmic reticulum (ER) and the plasma membrane, and Vps13A, a protein that tethers the ER to mitochondria and whose loss-of-function results in a neurodegenerative condition called chorea-acanthocytosis.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Talley, Edmund M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
Anatomy/Cell Biology
Schools of Medicine
New Haven
United States
Zip Code
Dong, Rui; Zhu, Ting; Benedetti, Lorena et al. (2018) The inositol 5-phosphatase INPP5K participates in the fine control of ER organization. J Cell Biol 217:3577-3592
Kumar, Nikit; Leonzino, Marianna; Hancock-Cerutti, William et al. (2018) VPS13A and VPS13C are lipid transport proteins differentially localized at ER contact sites. J Cell Biol 217:3625-3639
Benedetti, Lorena; Barentine, Andrew E S; Messa, Mirko et al. (2018) Light-activated protein interaction with high spatial subcellular confinement. Proc Natl Acad Sci U S A 115:E2238-E2245
Bian, Xin; Saheki, Yasunori; De Camilli, Pietro (2018) Ca2+ releases E-Syt1 autoinhibition to couple ER-plasma membrane tethering with lipid transport. EMBO J 37:219-234
Lees, Joshua A; Zhang, Yixiao; Oh, Michael S et al. (2017) Architecture of the human PI4KIII? lipid kinase complex. Proc Natl Acad Sci U S A 114:13720-13725
Gowrishankar, Swetha; Wu, Yumei; Ferguson, Shawn M (2017) Impaired JIP3-dependent axonal lysosome transport promotes amyloid plaque pathology. J Cell Biol 216:3291-3305
Stefan, Christopher J; Trimble, William S; Grinstein, Sergio et al. (2017) Membrane dynamics and organelle biogenesis-lipid pipelines and vesicular carriers. BMC Biol 15:102
Ritter, Brigitte; Ferguson, Shawn M; De Camilli, Pietro et al. (2017) A lentiviral system for efficient knockdown of proteins in neuronal cultures [version 1; referees: 2 approved]. MNI Open Res 1:
Cao, Mian; Wu, Yumei; Ashrafi, Ghazaleh et al. (2017) Parkinson Sac Domain Mutation in Synaptojanin 1 Impairs Clathrin Uncoating at Synapses and Triggers Dystrophic Changes in Dopaminergic Axons. Neuron 93:882-896.e5
Ma, Lu; Cai, Yiying; Li, Yanghui et al. (2017) Single-molecule force spectroscopy of protein-membrane interactions. Elife 6:

Showing the most recent 10 out of 102 publications