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When proteins misbehave (part 1)


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When proteins misbehave (part 1)

  1. 1. WHEN PROTEINS MISBEHAVE (Part 1)Before proteins can do their jobs, they have to be folded in a proper way. This isimportant because the shape determines the function of the protein. In 1990s we learnedthat wrongly folded proteins are involved in the development of many diseases. Now,protein folding has become a focus of attention in pharmaceutical research: it is probablethat new approaches to the treatment of diseases such as cancer, Parkinson’s disease,Alzheimer’s disease, ALS or schizophrenia to be found by studying protein misfolding.What is protein misfolding?Understanding this might require a trip back to high school biology class. Let’s beginwith the basics.Proteins are organic compounds made of amino acid strands. In order for a protein tocarry out its function, the linear strand of amino acids is carefully folded into a complexthree-dimensional structure. This folding process is fundamental to all of biology, but itremains a huge mystery to scientists.When proteins do not fold correctly, or misfold, they can aggregate together and form bigclumps in the cells where they form, causing diseases such as Alzheimer’s, Parkinson’s,multiple sclerosis (MS), diabetes, ALS, schizophrenia and many others..In neurobiology of chronic mental illnesses such as schizophrenia and bipolar disorderthe challenge becomes distinguishing the misfolded proteins from the normal, properlyfolded proteins in order to identify them as biological markers of these conditions.Protein folding diseases can be divided into two groups:1. Excessive quantities of wrongly folded proteins collect in the form of uncontrolledaggregates. This is the group of diseases known as amyloidoses, of whichAlzheimer’s disease is the best known example.2. incomplete folding of a protein, which affects its function. This might, for instance,happen to p53 protein in cancer. Normally, the p53 system is switched off. It isactivated inside a cell if the cell becomes excessively stressed or damaged, which canlead to genetic mutations in DNA that can cause the uncontrolled division andproliferation of cells that is the hallmark of tumors.What is a prion?A prion is a normal human protein which is a component of the membrane of healthynerve cells (called PrPc), which folds properly, remains soluble and is disposed ofwithout any particular problems. A prion protein can, however, misfold in a particularway, which allows it to take on an infectious, incorrectly folded three-dimensional form
  2. 2. (called PrPsc). The infectious prion, which can be transmitted in the diet, triggers adomino effect in healthy prions, forcing them to adopt its incorrectly folded form.Protein misfolding in schizophreniaA recently published study by Verian Bader, Philipp Ottis, Martin Pum, Joseph P.Huston, Carsten Korth from the Department of Neuropathology, Medical SchoolDüsseldorf, Germany, Center of Behavioral Neuroscience, University of Düsseldorfidentified a misfolded protein, called collapsin-response mediator protein 1 (CRMP1) asa marker for schizophrenia. Crimp1 is a protein expressed by the DISC1 gene involvedin schizophrenia. SFERA, MD