# Lipid Transfer at Membrane Contact Sites in Neuronal Function

> **NIH NIH R01** · YALE UNIVERSITY · 2021 · $365,048

## Abstract

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.

## Key facts

- **NIH application ID:** 10200151
- **Project number:** 5R01NS036251-25
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Pietro De Camilli
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $365,048
- **Award type:** 5
- **Project period:** 1997-05-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10200151

## Citation

> US National Institutes of Health, RePORTER application 10200151, Lipid Transfer at Membrane Contact Sites in Neuronal Function (5R01NS036251-25). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10200151. Licensed CC0.

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