Cholesterol transport protein emerges as possible target for Parkinson's treatment

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by Ingrid Fadelli, Medical Xpress

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Parkinson's disease (PD) is a neurodegenerative condition that causes the progressive loss of dopamine-producing neurons in a brain region called the substantia nigra. Its characteristic symptoms include tremors, slowed movements, rigid muscles and difficulties with balance.

While there is currently no cure for the disease, some medications can help to manage its symptoms. Understanding how PD damages dopamine-producing neurons could help to develop new treatments that effectively slow down the disease's progression.

Past studies have uncovered a link between PD and an accumulation of cholesterol in the brain. Attempts to slow down the disease by reducing cholesterol production, however, have had limited success so far.

Researchers at Nanjing Medical University set out to explore the possible contribution of ATP-binding cassette transporter A1 (ABCA1), a protein that transports cholesterol in the brain, to PD.

The results of their study, published in Nature Neuroscience, suggest that this protein plays a role in the accumulation of cholesterol linked to PD-related neuronal damage, while also identifying a new possible molecular target for treating the disease.

Tracing cholesterol transport between brain cells

The researchers analyzed data derived from postmortem tissue of patients with PD, focusing on changes in cholesterol-related pathways and the expression of ABCA1. They also studied mouse models that reproduce some PD characteristics and cells grown in a laboratory setting.

Their main goal was to better understand how ABCA1 expression affects the transport and accumulation of cholesterol. Their analyses thus also examined astrocytes, brain cells involved in supplying neurons with cholesterol.

"We identify ABCA1 as a critical regulator of cholesterol homeostasis in PD," wrote Feng-xia Ma, Xin-xin Zhao and their colleagues in their paper. "We show that ABCA1 expression is elevated in the substantia nigra of postmortem PD brains and in a PD mouse model, with regional analyses revealing preferential alterations in nigral and striatal circuits."

The team's analyses revealed that ABCA1 in astrocytes drove an excessive release of cholesterol, contributing to its accumulation in neurons. ABCA1 in neurons, on the other hand, appeared to facilitate the entry of cholesterol into lysosomes, small compartments inside cells that break down and recycle unwanted materials.

The team found that cholesterol subsequently accumulated inside lysosomes, impairing cellular recycling processes and leading to an unusual buildup of the protein α-synuclein. This protein, which usually helps to regulate communication between nerve cells, can fold abnormally in the brains of people with PD and form clumps, contributing to neuronal damage.

Altered brain cholesterol synthesis and transport in Parkinson's disease and mouse models. a) Analysis of gene-expression data showing altered pathways in the substantia nigra of patients with Parkinson's disease. b) Experimental design of the 6-OHDA mouse model. c) Staining and quantification of cholesterol, dopamine-producing neurons and astrocytes in this model. d, e) Cholesterol levels in the striatum and substantia nigra. f) Experimental design of the PFF mouse model. g) Staining and quantification of cholesterol, dopamine-producing neurons and astrocytes in this model. h) Cholesterol levels in the striatum and substantia nigra. i) Relationships between cholesterol levels and markers of dopamine-producing neurons and astrocytes. j) Expression of cholesterol metabolism-related genes in the substantia nigra. k) ABCA1 expression in the substantia nigra of patients with Parkinson's disease and healthy controls across three gene-expression data sets. Credit: Ma et al. (Nature Neuroscience, 2026).

A possible target for future Parkinson's treatments

During their experiments, the team also tried silencing the Abca1 gene and reducing the production of the ABCA1 protein in the mouse brain using genetically engineered viruses, called adeno-associated viruses (AAVs). In the mouse model of PD, silencing the gene reduced neuronal damage and PD-like motor impairments.

"Genetic silencing of Abca1 in either astrocytes or dopaminergic neurons attenuates neurodegeneration and behavioral deficits in vivo," wrote the authors.

Ma, Zhao and their colleagues also screened different substances to identify ones that inhibit ABCA1 activity. One of them, magnesium citrate, reduced dopamine-producing neuronal loss in the mouse model.

"We identify magnesium citrate as an ABCA1 inhibitor and show that it reduces dopaminergic neuronal loss in a PD mouse model," wrote Ma, Zhao and their colleagues. "Our findings identify an ABCA1-dependent cholesterol pathway underlying PD pathogenesis and support ABCA1 inhibition as a potential disease-modifying strategy."

This recent study could open a new route for the study of PD and contribute to ongoing efforts to develop effective treatments. Notably, the beneficial effects of magnesium citrate have not been established in humans. Studies with other animal models of PD confirming the substance's therapeutic potential could eventually pave the way for human clinical trials.

Written for you by our author Ingrid Fadelli, edited by Sadie Harley, and fact-checked and reviewed by Robert Egan—this article is the result of careful human work. We rely on readers like you to keep independent science journalism alive. If this reporting matters to you, please consider a donation (especially monthly). You'll get an ad-free account as a thank-you.

Publication details

Feng-xia Ma et al., Dysregulated cholesterol trafficking through ABCA1 drives neurodegeneration in Parkinson's disease, Nature Neuroscience (2026). DOI: 10.1038/s41593-026-02487-7.

Journal information: Nature Neuroscience

Key medical concepts

Parkinson's DiseaseABCA1 protein, humanCholesterolalpha-Synuclein

Clinical categories

Neurology Who's behind this story?

Ingrid Fadelli

Freelance journalist with BSc Psychology and MA International Journalism. Covers AI, robotics, neuroscience, and astrophysics since 2018. Full profile →

Sadie Harley

BSc Life Sciences & Ecology. Microbiology lab background with pharmaceutical news experience in oil, gas, and renewable industries. Full profile →

Robert Egan

Bachelor's in mathematical biology, Master's in creative writing. Well-traveled with unique perspectives on science and language. Full profile →

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