Prions Link Cholesterol To Neurodegeneration

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Prions Link Cholesterol To Neurodegeneration

http://www.sciencedaily.com/releases/2008/02/080211195230.htm

Prion infection of neurons increases the free cholesterol content in

cell membranes. A new study suggests that disturbances in membrane

cholesterol may be the mechanism by which prions cause

neurodegeneration and could point to a role for cholesterol in other

neurodegenerative diseases.

It is widely believed that prions (protein only infectious material)

are the cause of rare progressive neurodegenerative disorders that

affect both humans and animals. A prion is an infectious agent made

solely of protein. However what is not known is how the prions damage

brain cells (neurons).

Dr Clive Bate and colleagues from the Royal Veterinary College in the

UK compared the amounts of protein and cholesterol in prion-infected

neuronal cell lines and primary cortical neurons with uninfected

controls. Protein levels were similar but the amount of total

cholesterol (a mixture of free and esterified cholesterol) was

significantly higher in the infected cell lines.

The cholesterol balance was also affected: the amount of free

cholesterol increased but that of cholesterol esters reduced,

suggesting that prion infection affects cholesterol regulation. The

team attempted to reproduce the effects of prions on cholesterol

levels, by stimulating cholesterol biosynthesis or by adding

exogenous cholesterol. Both approaches resulted in increased amounts

of cholesterol esters but not of free cholesterol.

The free cholesterol is thought to affect the function of the cell

membranes and to lead to abnormal activation of phospholipase A2, an

enzyme implicated in the depletion of neurons in prion and

Alzheimer's disease.

Studies have recently shown that the controlling cholesterol levels

within the brain is critical in limiting the development of

neurodegenerative diseases such as Alzheimer's, Parkinson's and prion

diseases, multiple sclerosis, and senile dementia. This study now

gives far more specific insight into the kind of mechanisms at work.

Dr Bate stated: " Our observations raise the possibility that

disturbances in membrane cholesterol induced by prions are major

triggering events in the neuropathogenesis of prion diseases " .

Journal reference: Sequestration of free cholesterol in cell

membranes by prions correlates with cytoplasmic phospholipase A2

activation. Clive Bate, Mourad Tayebi and Alun . BMC Biology

(in press).