# Lysosomal control of plasma membrane -endoplasmic reticulum membrane contacts regulates neuronal excitability

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2024 · $402,500

## Abstract

Project Summary
Lysosomes are sophisticated and dynamic cellular signaling centers that control metabolism, gene transcription,
calcium (Ca2+) homeostasis, and autophagy. A key mechanism through which lysosomes communicate and
receive instruction is via transfer of cholesterol at ER–lysosome membrane contact sites. At these contacts the
Niemann Pick C1 cholesterol transporter (NPC1) facilitates the efflux of cholesterol out of the lysosome before
it is transferred to the ER for distribution to other cellular membranes. Thus, NPC1 is a key gatekeeper in
cholesterol metabolism. Further underscoring its importance, loss of function mutations in NPC1 lead to the
progressive neurodegenerative disorder, NPC disease. This fatal condition has no cure and is characterized by
the accumulation of cholesterol within lysosome lumen and the progressive neurodegeneration of several brain
regions that are accompanied by a host of devastating symptoms including seizures, psychiatric problems, and
dementia. Notwithstanding clear neuropathological consequences for cholesterol dysregulation in NPC disease,
the molecular mechanism(s) linking loss of NPC1 function to disease neuropathology are unknown. Recently
our group has reported that loss of NPC1 function results in (i) neuron hyperexcitability, (ii) reorganization of ER–
Lysosome, ER–Golgi, and ER–mitochondrial membrane contact sites, and (iii) induces neurotoxic increases in
mitochondrial Ca2+. Despite this crucial information there are critical gaps in our knowledge regarding (1) the
consequences of enhanced excitability in NPC disease, (2) how lysosomal cholesterol transport alters the
molecular elements and choreography at neuronal ER–plasma membrane (ER–PM) contact sites, and (3) if
plasma membrane ion channels or ER–PM junctions can be targeted to reduce mitochondrial toxicity and
increase neuron viability in NPC disease. Our central hypothesis is that loss of NPC1 function results in
aberrant remodeling of ion channel distribution and function at ER–PM contacts to drive cytotoxic increases in
mitochondrial Ca2+ leading to neurodegeneration. To test this hypothesis, we implement a multi-scale approach,
including super-resolution imaging, electrophysiology, optical mapping of brain excitability, novel murine models,
and animal behavior testing to rigorously investigate the mechanisms by which cholesterol efflux from the
lysosome tunes neuron viability. The fundamental importance and ubiquitous expression of the NPC cholesterol
transporter means we should pay particular attention to molecular elements and signaling cascades that are
modified by its activity. Investigating the relationship between cholesterol homeostasis and ion channel signaling
at ER–PM membrane contacts in NPC provides a testable model for examining the interdependence of
lysosomal cholesterol and ion channel activity and has broad implications for several fields and other cholesterol-
linked diseases such as Alzheimer’s and Parkinson’s.

## Key facts

- **NIH application ID:** 10868443
- **Project number:** 5R35GM149211-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Eamonn James Dickson
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $402,500
- **Award type:** 5
- **Project period:** 2023-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10868443

## Citation

> US National Institutes of Health, RePORTER application 10868443, Lysosomal control of plasma membrane -endoplasmic reticulum membrane contacts regulates neuronal excitability (5R35GM149211-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10868443. Licensed CC0.

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