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Wuhan, China – A groundbreaking study led by Zhentao Zhang at Wuhan University has identified a cholesterol metabolite that plays a crucial role in the development of Parkinson’s disease in mice. Published in the journal PLOS Biology, the research suggests that this metabolite contributes to the formation of Lewy bodies and the degeneration of dopaminergic neurons—two key hallmarks of Parkinson’s disease. The findings open up new avenues for potential treatment strategies aimed at blocking its activity or preventing its formation.
Parkinson’s disease is characterized by the accumulation of alpha-synuclein (alpha-Syn) proteins into clumps known as Lewy bodies, which spread throughout the brain and eventually lead to the death of dopamine-producing neurons. The study focused on identifying the factors that drive this process, with researchers suspecting that 24-hydroxycholesterol (24-OHC), a cholesterol metabolite, may be a major contributor. This metabolite is known to be present at high levels in the brains of Parkinson’s patients and increases with age.
The researchers confirmed that 24-OHC levels were elevated in the blood of Parkinson’s disease patients as well as in a mouse model of the disease. They then genetically modified mice to block the production of 24-OHC by knocking out the enzyme responsible for its formation. This intervention significantly reduced the spread of harmful alpha-Syn fibers and lessened the damage to dopamine neurons in key areas of the brain.
Further laboratory experiments demonstrated that introducing 24-OHC to cultured neurons induced the transformation of normal alpha-Syn into harmful fibers. Mice injected with these pathological fibers exhibited increased Lewy body spread, greater neuron degeneration, and more pronounced motor deficits compared to those injected with alpha-Syn fibers formed without 24-OHC. These findings suggest that drugs targeting the conversion of cholesterol into 24-OHC could be an effective approach to treating Parkinson’s disease.
“Our findings indicate that the cholesterol 24-hydroxylase CYP46A1 plays a pivotal role in the progression of alpha-synuclein pathology in Parkinson’s disease, highlighting its potential as a therapeutic target,” the study authors stated.
The discovery marks a significant step toward understanding the molecular mechanisms underlying Parkinson’s disease and provides a potential pathway for the development of novel treatments.
Disclaimer: This article is based on a preclinical study conducted on mice and cultured cells. Further research, including clinical trials, is necessary to confirm these findings in humans before any therapeutic applications can be developed.
