Cholesterol byproduct may be therapeutic target for Parkinson’s
Compound called 24-OHC linked to formation of toxic alpha-synuclein clumps
A compound formed by nerve cells as they break down cholesterol appears to be involved in the formation of toxic alpha-synuclein protein clumps in the brain — clumps, or aggregates, that are tied to Parkinson’s disease — making this byproduct a potential therapeutic target, a new study in patients and mice suggests.
That cholesterol metabolism byproduct, a compound known as 24-OHC, was linked to alpha-synuclein aggregates, which lead to the death of dopaminergic neurons, the nerve cells that produce the chemical messenger dopamine.
Both 24-OHC and the cholesterol 24-hydroxylase CYP46A1, the enzyme needed to convert it from cholesterol, were elevated in the blood and brain of patients and mice modeling the disease, the study found. According to the researchers, from Wuhan University in China, that suggests they may be molecular targets in the treatment of Parkinson’s.
“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 scientists said in a press release.
Their study, “The cholesterol 24-hydroxylase CYP46A1 promotes [alpha]-synuclein pathology in Parkinson’s disease,” was published in the journal PLOS Biology.
Compound ID’d as therapeutic target ‘crucial’ in alpha-synuclein clumping
In Parkinson’s, toxic forms of the alpha-synuclein protein fold into an unusual shape that make it prone to clumping into small structures known as fibrils. These fibrils can spread from one cell to the next, and come together to form Lewy bodies in the brain, a hallmark of the disease.
Lewy bodies drive the death of dopaminergic neurons, the nerve cells in the brain that produce dopamine, a chemical involved in motor control. A gradual shortage of dopamine results in progressive motor symptoms, such as slowness and stiffness, tremor, and difficulty walking and keeping balance.
While cholesterol-lowering medications have been suggested to help ease motor symptoms in animal models of Parkinson’s, how exactly they work is unclear. Here, the researchers focused on 24-OHC, a cholesterol byproduct formed in the brain by the action of CYP46A1.
The team found that 24-OHC was present at significantly higher levels in the blood of patients with a clinically confirmed diagnosis of Parkinson’s compared with control individuals of similar age. Levels of CYP46A1 were also elevated in postmortem brain samples from patients.
To model Parkinson’s, the researchers used mice in which A53T, a mutant form of human alpha-synuclein known to cause familial Parkinson’s, results in the death of dopaminergic neurons. In these mice, levels of 24-OHC and CYP46A1 were increased relative to wild-type animals and tended to become more abundant with age, suggesting they may be linked to how the disease progresses. There also was an age-dependent increase in the levels of both of these compounds in wild-type animals.
When CYP46A1 was overproduced, it worsened the buildup of toxic alpha-synuclein protein clumps. Decreasing its level, meanwhile, prevented the death of dopaminergic neurons in mice.
These results suggest that CYP46A1 and 24-OHC play crucial roles in … [alpha-synuclein] pathology. … Strategies aimed at inhibiting [protein activity linked to cholesterol metabolism] could hold promise as disease-modifying therapies for [Parkinson’s].
Blocking the production of 24-OHC by knocking out the CYP46A1 enzyme reduced both the spread of the toxic alpha-synuclein protein clumps and prevented the death of dopaminergic neurons.
This happened through increased activity of two proteins, XBP1 and LAG3, which play a role in cellular stress and immune response.
Treating nerve cells in the lab with 24-OHC increased the formation of alpha-synuclein clumps. When mice were injected with these 24-OHC-induced fibers, there was increased spread of Lewy bodies, a higher rate of dopamine-producing neuron deterioration, and more severe motor impairments relative to mice injected with alpha-synuclein fibers that were not formed in the presence of 24-OHC.
“These results suggest that CYP46A1 and 24-OHC play crucial roles in … [alpha-synuclein] pathology,” the researchers wrote. “Strategies aimed at inhibiting the CYP46A1-24-OHC axis and LAG3 could hold promise as disease-modifying therapies for [Parkinson’s].”
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