The protein Srebp2 drives cholesterol formation in prion-infected neuronal cells

November 18, 2009

Prions are causing fatal and infectious diseases of the nervous system, such as the mad cow disease (BSE), scrapie in sheep or Creutzfeldt-Jakob disease in humans. Scientists of Helmholtz Zentrum München and Technische Universität München, Germany, have now succeeded in elucidating another disease mechanism of prion diseases: The prion-infected cell changes its gene expression and produces increased quantities of cholesterol. Prions need this for their propagation.

Prions are infectious and transform the brains of humans and animals into sponge-like structures. Unlike a virus, a prion only consists of protein - called prion-protein in its pathological form (PrPSc). Until now, little was known about the processes that take place inside the infected neuronal cell. This made it difficult to develop effective drugs against prion diseases.

Using microarrays developed in the lab of Dr. Johannes Beckers, Christian Bach and colleagues from Helmholtz Zentrum München and Technische Universität made a genome-wide analysis of gene activity in prion-infected and healthy cells. The researchers found over 100 genes which are differentially expressed in infected and healthy cells. This has serious consequences for the : "Several enzymes of cholesterol biosynthesis are affected", explained Christian Bach, first author of the study. As a consequence, the cholesterol level rises in the infected cells.

The cause of this development is the increased activity of the regulating protein Srebp2. It switches on the genes that are involved in cholesterol biosynthesis and cellular uptake. To achieve this, Srebp2 binds to a special segment encoding the gene to be transcribed - the sterol regulatory element. This activates the gene, leading to the biosynthesis of the corresponding protein.

In every step of cholesterol biosynthesis Srebp2 switches on different genes, thus exactly controlling , i.e. the translation of gene information into the corresponding protein. If cholesterol concentration is elevated in a healthy cell, Srebp2 remains in its inactive form and does not bind to the sterol regulatory element. This control mechanism is obviously disturbed in the infected cells, causing increased cholesterol synthesis. "Remarkably, only neuronal cells react in this way - microglia cells exposed to prions do not increase their cholesterol production," said Professor Hermann Schätzl of the Institute of Virology of Technische Universität München, who led the research together with Dr. Ina Vorberg. Further studies shall elucidate what role disturbed regulation plays in neuronal cells for the development of prion diseases and shall thus point the way to new therapy approaches.

More information: Prion-Induced Activation of Cholesterogenic Gene Expression by a Sterol Regulatory Element Binding Protein (Srebp2) in , Journal Biological Chemistry Vol 284, No. 45, pp 31260-31269 Nov 2009.

Source: Helmholtz Zentrum München

Explore further: Prions link cholesterol to neurodegeneration

Related Stories

Prions link cholesterol to neurodegeneration

February 12, 2008

Prion infection of neurons increases the free cholesterol content in cell membranes. A new study published in the online open access journal BMC Biology suggests that disturbances in membrane cholesterol may be the mechanism ...

Prions show their good side

May 7, 2008

Prions, the infamous agents behind mad cow disease and its human variation, Creutzfeldt-Jakob Disease, also have a helpful side. According to new findings from Gerald Zamponi and colleagues, normally functioning prions prevent ...

Is there more to prion protein than mad cow disease?

September 30, 2008

Prion protein, a form of protein that triggers BSE, is associated with other brain diseases in cattle, raising the possibility of a significant increase in the range of prion disease. Publishing their findings in the open ...

Prion discovery gives clue to control of mass gene expression

March 13, 2009

The discovery in common brewer's yeast of a new, infectious, misfolded protein -- or prion -- by University of Illinois at Chicago molecular biologists raises new questions about the roles played by these curious molecules, ...

New prion protein may offer insight into mad cow disease

August 22, 2007

Scientists have discovered a new protein that may offer fresh insights into brain function in mad cow disease. Research led by Dr. David Westaway has led to the first discovery since 1985 of a new brain prion protein.

Recommended for you

Power stations driven by light

January 16, 2019

Green plants, algae and some bacteria use sunlight to convert energy. The pigments in chlorophyll absorb electromagnetic radiation, which induces chemical reactions in electrons. These reactions take place in the nucleus ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.