# Abnormalities of cholesterol metabolism in multiple system atrophy

> **NIH NIH R21** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $205,625

## Abstract

Summary
 Multiple system atrophy, or MSA, is the most common cause of adult-onset neurodegenerative ataxia, and so
far, no disease-modifying therapy has been developed. One of the reasons for this lack of therapy is that the
etiology of MSA remains unclear, though several possible mechanisms have been proposed. Defects in the
synthesis and levels of Coenzyme Q (ubiquinone, CoQ), a lipophillic molecule present in virtually all cell
membranes, represent a common phenomenon in MSA, with or without mutations in the COQ2 gene, which
encodes 4-para-hydroxybenzoate polyprenyl transferase, the second enzyme involved in CoQ10 biosynthesis.
The essential role of CoQ in mitochondrial oxidative phosphorylation has been explored in the context of
neurodegenerative disease such as MSA. However, other aspects of CoQ biology, such as its role in the
regulation of cholesterol metabolism, have not been investigated.
 Cholesterol homeostasis is maintained in the cell by a tightly-regulated balance between its de novo synthesis,
and its internalization from extracellular lipoproteins. Alterations in this balance result in neuronal dysfunction.
 The biosynthesis of cholesterol and CoQ are two co-regulated branches of the mevalonate pathway. As such,
stimulation of cholesterol biosynthesis also results in increases in CoQ production; thus, decrease in CoQ levels
should result in the subsequent activation of the mevalonate pathway and the de novo synthesis of cholesterol,
followed by inhibition of the internalization of extracellular cholesterol, to maintain homeostasis. We propose
that defects in CoQ biosynthesis induce cell dysfunction by alterations in cholesterol homeostasis via sustained
downregulation of cholesterol internalization (AIM 1).
 Our published data showed that decrease in the internalization of cholesterol, but not its synthesis, results in
defects in the formation of mitochondria-associated ER membranes (MAM) domains, an ER lipid-raft involved in
the modulation of multiple metabolic pathways, including the regulation of lipid homeostasis. Notably, defects in
the formation of MAM domains have been observed in neurodegenerative diseases such as AD, PD and ALS.
Recently, CoQ synthesis has been shown to be regulated at MAM domains in yeast. However, whether this is
also the case in human cells it not known.
 Based on our preliminary data, we propose a novel mechanism by which CoQ defects, via inhibition of
cholesterol internalization, impair the formation of MAM domains and the inhibition of the activities localized in
this domain (AIM 2).
 Our results will elucidate the interplay between CoQ, cholesterol metabolism and MAM function, and its
contribution to neuronal demise in MSA, and other neurodegenerative diseases.

## Key facts

- **NIH application ID:** 10792884
- **Project number:** 5R21AG077243-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Catarina M. Quinzii
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $205,625
- **Award type:** 5
- **Project period:** 2023-03-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10792884

## Citation

> US National Institutes of Health, RePORTER application 10792884, Abnormalities of cholesterol metabolism in multiple system atrophy (5R21AG077243-02). Retrieved via AI Analytics 2026-06-13 from https://api.ai-analytics.org/grant/nih/10792884. Licensed CC0.

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