Illustration depicting tangled proteins inside a neuron with a spotlight on 27-hydroxycholesterol.

Unlocking the Mystery: How 27-Hydroxycholesterol Impacts Brain Health

Theo Raines in Health & Wellness August 2025 • 4 min read.

"New Research Reveals a Link Between Cholesterol Metabolites and Parkinson's Disease."

Parkinson's disease (PD) is a neurodegenerative disorder affecting millions worldwide. While the exact causes of PD remain elusive, scientists are increasingly focused on understanding the role of specific proteins and metabolic processes in its development. A hallmark of PD and related disorders (synucleinopathies) is the abnormal accumulation of a protein called alpha-synuclein (α-syn) in brain cells.

Recent research has begun to explore the connection between cholesterol metabolism and synucleinopathies. One particular molecule, 27-hydroxycholesterol (27-OHC), a major cholesterol metabolite that can cross the blood-brain barrier, has come under scrutiny. Elevated levels of 27-OHC have been observed in individuals with hypercholesterolemia, aging, and oxidative stress – all factors associated with an increased risk of synucleinopathies.

A groundbreaking study published in BMC Neuroscience sheds new light on how 27-OHC impacts α-syn levels within human dopaminergic neurons, the very cells affected in Parkinson's disease. By understanding this connection, researchers hope to unlock potential therapeutic targets for preventing or slowing the progression of PD.

The 27-OHC Connection: What the Study Reveals

Illustration depicting tangled proteins inside a neuron with a spotlight on 27-hydroxycholesterol.

The BMC Neuroscience study, led by Jared Schommer and Othman Ghribi, investigated the effects of 27-OHC on α-syn levels in human dopaminergic neurons. The research team's findings suggest a significant link between 27-OHC and increased α-syn protein levels, potentially mediated through the disruption of protein degradation pathways within these brain cells.

Here's a breakdown of the key findings:

Increased α-Synuclein Protein: The study demonstrated that 27-OHC significantly increases α-syn protein levels in human dopaminergic neurons. Importantly, this increase was observed at the protein level, not at the messenger RNA (mRNA) level, suggesting a post-translational mechanism (i.e., affecting the protein after it's been produced).
LXR Independence: Liver X receptors (LXRs) are proteins that regulate gene expression in response to oxysterols like 27-OHC. The researchers found that the effects of 27-OHC on α-syn were independent of LXR activation, suggesting an alternative pathway at play.
Proteasomal Inhibition: The study points to the inhibition of the proteasome, a cellular machine responsible for degrading damaged or misfolded proteins, as a key mechanism. 27-OHC appears to impair proteasome function, leading to reduced degradation of α-syn and its subsequent accumulation.
HSP70 Reduction: Heat shock protein 70 (HSP70) is involved in protein folding and degradation. The research indicated that 27-OHC reduces HSP70 levels, potentially further disrupting protein homeostasis and contributing to α-syn accumulation.

These results suggest that 27-OHC's influence on α-syn levels stems from hindering the normal protein disposal processes within dopaminergic neurons. This disruption can have significant implications for the development of synucleinopathies.

What Does This Mean for Future Research and Treatment?

The identification of 27-OHC as a factor capable of increasing α-syn levels, along with the discovery of proteasomal dysfunction and HSP70 reduction as potential mechanisms, opens exciting new avenues for research and therapeutic development. Future studies can focus on:

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Everything You Need To Know

What is 27-hydroxycholesterol?

27-hydroxycholesterol (27-OHC) is a major cholesterol metabolite that can cross the blood-brain barrier. It's significant because elevated levels of 27-OHC have been observed in individuals with hypercholesterolemia, aging, and oxidative stress, all factors associated with an increased risk of synucleinopathies like Parkinson's disease. Its presence in the brain suggests a direct link between cholesterol metabolism and neurodegenerative processes.

What is alpha-synuclein, and why is it important in the context of Parkinson's?

Alpha-synuclein (α-syn) is a protein found in brain cells. In Parkinson's disease and related disorders (synucleinopathies), α-syn abnormally accumulates in brain cells, forming what are known as Lewy bodies. This accumulation disrupts normal neuronal function and is a hallmark of these diseases. Understanding what causes this build-up is crucial for developing effective treatments.

What were the main findings regarding 27-hydroxycholesterol's impact on alpha-synuclein levels?

The study found that 27-hydroxycholesterol (27-OHC) significantly increases alpha-synuclein (α-syn) protein levels in human dopaminergic neurons. It appears 27-OHC impairs the proteasome function, which is normally responsible for degrading damaged or misfolded proteins, leading to reduced degradation of α-syn and its subsequent accumulation. Also, 27-OHC reduces Heat shock protein 70 (HSP70) levels, potentially further disrupting protein homeostasis and contributing to α-syn accumulation. These are key findings because they highlight a specific mechanism by which cholesterol metabolism can influence the development of Parkinson's disease.

What is the role of the proteasome, and why is its inhibition significant?

The proteasome is a cellular machine responsible for degrading damaged or misfolded proteins. Its function is vital for maintaining cellular health by preventing the accumulation of toxic protein aggregates. When the proteasome is inhibited, as suggested in the study with 27-hydroxycholesterol (27-OHC), proteins like alpha-synuclein (α-syn) are not efficiently broken down, leading to their build-up and potential neuronal dysfunction, which is implicated in diseases like Parkinson's.

What is the role of Heat shock protein 70 (HSP70) in relation to 27-hydroxycholesterol and the study?

Heat shock protein 70 (HSP70) is involved in protein folding and degradation. The study indicated that 27-hydroxycholesterol (27-OHC) reduces HSP70 levels, potentially further disrupting protein homeostasis and contributing to α-syn accumulation. By maintaining proteins in their correct shape and aiding in the removal of misfolded ones, HSP70 prevents the formation of toxic aggregates that can harm cells.