Protein Misfolding in Psychiatry
Before proteins can do their jobs, they have to be folded in a proper way. This is
important because the shape determines the function of the protein. In 1990s we learned
that 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 probable
that 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 begin
with the basics.
Proteins are organic compounds made of amino acid strands. In order for a protein to
carry out its function, the linear strand of amino acids is carefully folded into a complex
three-dimensional structure. This folding process is fundamental to all of biology, but it
remains a huge mystery to scientists.
When proteins do not fold correctly, or misfold, they can aggregate together and form big
clumps 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 disorder
the challenge becomes distinguishing the misfolded proteins from the normal, properly
folded 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 uncontrolled
aggregates. This is the group of diseases known as amyloidoses, of which
Alzheimer’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 is
activated inside a cell if the cell becomes excessively stressed or damaged, which can
lead to genetic mutations in DNA that can cause the uncontrolled division and
proliferation 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 healthy
nerve cells (called PrPc
), which folds properly, remains soluble and is disposed of
without any particular problems. A prion protein can, however, misfold in a particular
way, which allows it to take on an infectious, incorrectly folded three-dimensional form
). The infectious prion, which can be transmitted in the diet, triggers a
domino effect in healthy prions, forcing them to adopt its incorrectly folded form.
Protein misfolding in schizophrenia
A recently published study by Verian Bader, Philipp Ottis, Martin Pum, Joseph P.
Huston, Carsten Korth from the Department of Neuropathology, Medical School
Düsseldorf, Germany, Center of Behavioral Neuroscience, University of Düsseldorf
identified a misfolded protein, called collapsin-response mediator protein 1 (CRMP1) as
a marker for schizophrenia. Crimp1 is a protein expressed by the DISC1 gene involved
ADONIS SFERA, MD