A groundbreaking study by researchers at Wuhan University, China, has identified a cholesterol metabolite that plays a crucial role in the progression of Parkinson’s disease. The findings, published in the open-access journal PLOS Biology, suggest that blocking this metabolite could be a potential strategy for treating the neurodegenerative disorder.
The study, led by Zhentao Zhang, focuses on 24-hydroxycholesterol (24-OHC), a cholesterol metabolite that appears to accelerate the formation of Lewy bodies and the death of dopaminergic neurons—two major hallmarks of Parkinson’s disease. The research highlights how 24-OHC contributes to the spread of pathological alpha-Synuclein (alpha-Syn) fibres, which are responsible for neuron damage in the brain.
Parkinson’s disease develops when alpha-Syn proteins clump together, forming toxic Lewy bodies that spread from one brain cell to another, leading to the degeneration of dopamine-producing neurons. Previous studies have shown that 24-OHC levels are elevated in the brains of Parkinson’s patients and increase with age, prompting the Wuhan University team to investigate whether this metabolite directly contributes to disease progression.
By analyzing blood samples from Parkinson’s patients and a mouse model of the disease, the researchers confirmed that 24-OHC levels were significantly elevated. To explore its impact, they genetically modified mice to block the enzyme responsible for producing 24-OHC from cholesterol. This intervention significantly reduced the spread of harmful alpha-Syn fibres and minimized neuron damage in key brain regions associated with Parkinson’s disease.
Further experiments using lab-grown neuron cultures demonstrated that adding 24-OHC triggered normal alpha-Syn proteins to transform into toxic fibres. When these modified fibres were injected into mice, they exhibited increased Lewy body formation, greater neuron loss, and more severe motor function impairment compared to those injected with alpha-Syn fibres that lacked 24-OHC exposure.
The findings suggest that drugs targeting cholesterol metabolism—specifically, preventing cholesterol from converting into 24-OHC—could offer a promising treatment for Parkinson’s disease. The study’s authors emphasize the potential of cholesterol 24-hydroxylase CYP46A1, the enzyme responsible for producing 24-OHC, as a novel therapeutic target.
“Our findings indicate that cholesterol 24-hydroxylase CYP46A1 plays a pivotal role in the progression of alpha-Syn pathology in Parkinson’s disease, highlighting its potential as a therapeutic target,” the researchers stated.
With Parkinson’s disease affecting millions worldwide, these findings pave the way for new drug development and treatment strategies, offering hope for patients and researchers seeking effective interventions for the disease.
