# Membrane contact sites regulate cellular excitability

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2021 · $314,000

## Abstract

The long-term goal of this proposal is to develop therapeutic strategies for the treatment of a human disease
characterized by pathological changes in cellular cholesterol metabolism, Niemann-Pick type C (NPC) disease.
NPC disease is a fatal neurodegenerative disorder that occurs due to mutations within a key gatekeeper
protein in cholesterol transport: lysosomal Niemann-Pick type C1. Neurons from NPC patients have
dramatically altered cholesterol homeostasis due to reduce transport of cholesterol out of lysosomes to the
endoplasmic reticulum. Neurologically, accumulation of lysosomal cholesterol in NPC patient neurons, gives
rise to impaired motor functions, psychiatric problems, seizures, dementia, and typically death prior to
adulthood. Despite clear neuropathological consequences for cholesterol dysregulation in NPC disease, there
has been little research attention invested in understanding whether altered ion channel function, neuronal
excitability, and calcium handling, contribute to the neuropathology of NPC disease. Given that
phosphoinositides control a wide range of cellular processes including the regulation of plasma membrane ion
channel activity, it follows that any interdependence in the membrane pools of these lipids could have critically
important implications for this disease. Our central hypothesis is that regulated efflux of cholesterol from
lysosomes to the ER, via NPC1, is a rheostat for phosphoinositides and consequently neuronal excitability. To
test this hypothesis, we implement a multi-scale approach to rigorously investigate the mechanisms by which
cholesterol can regulate the abundance and distribution of phosphoinositides to alter phosphoinositide-
dependent ion channel function. Specific Aim 1 will test the hypothesis that alterations in NPC1 function
modifies plasma membrane phosphoinositides, to alter ion channel activity, and consequently neuron
membrane excitability and function. In Specific Aim 2 we test the hypothesis that alterations in excitability and
membrane cholesterol controls the ability of neurons to store and release calcium. Finally, in Specific Aim 3
we will determine specific proteins that have their expression profiles altered in NPC to modify
phosphoinositide-dependent ion channel function. The proposed studies have specific relevance in the fields of
neuroscience, cell biology and biophysics, but the fundamental importance of phosphoinositides and
cholesterol for a plethora of cellular events, mean it will have broad implications for medicine.

## Key facts

- **NIH application ID:** 10061627
- **Project number:** 5R01GM127513-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Eamonn James Dickson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $314,000
- **Award type:** 5
- **Project period:** 2019-01-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10061627

## Citation

> US National Institutes of Health, RePORTER application 10061627, Membrane contact sites regulate cellular excitability (5R01GM127513-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10061627. Licensed CC0.

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