Proteopathy

As protein misfolding diseases, including protein folding diseases ( engl. protein misfolding diseases or protein misfolding disorders or conformational diseases ) called, referred to such diseases caused by misfolded proteins. The incorrectly folded proteins are either stored in the cells or degraded in the proteasome. In the first case this form toxic deposits (plaques ) in the second enters a loss of function due to a lack of the corresponding protein in the cell or the entire organism, a. Both can become pathological and depending on the affected protein lead to different diseases over time for those affected.

Biochemical mechanism

In most cells of all organisms a variety of proteins ( proteins) are produced in the context of protein constantly, which fulfill different functions in the cell and the whole organism. For correct function of a protein whose tertiary structure is crucial. This structure is achieved by a process of protein folding is called. Protein folding is a complex and delicate procedure. The correct protein folding is monitored by the protein quality control. About 30 % of all proteins are not properly folded Statistically from the protein and usually degraded within about ten minutes in the proteasome of the cell.

A single misfolded protein molecule is not responsible for the severe diseases of protein misfolding diseases. For large quantities of these proteins must arise or reduce the number of correctly folded molecules. In prion this happens because a misfolded molecule in contact with a correctly folded molecule the correct prompted them to unfold and fold last wrong again. Since the first misfolded protein is not changed by this operation ( so it works as an enzyme ), after two misfolded molecules are present. This can further correct molecules refold.

The faulty proteins are also called defective ribosomal products ( engl. defective ribosomal products, DRiPs ).

Causes

The reasons for an incorrect protein folding are complex. Gene mutations in exons which lead to changes in the amino acid sequence that is the primary structure of the gene, have a direct influence on the secondary and tertiary structure, or to the Proteinfaltungskinetik. Also errors in the transcription or translation may lead to misfolding of proteins. Another possible factor is the environment; so with the infectious prion diseases, the prion protein is taken with food or transmitted by surgical instruments. Meanwhile, there are also first indications of a produced by cycads and cyanobacteria toxin ( BMAA ), which, thus possibly through its incorporation into proteins whose misfolding to a form of ALS.

Gain -of -toxic -function

Can the DRiPs not be removed, for example, because they have been assembled into aggregates in the proteasome, then the DRiPs accumulate in the cell. There, they can become pathological over time, that is, lead to specific diseases. The protein aggregates lead mainly to neurodegenerative diseases such as Parkinson 's disease, Alzheimer 's disease or Huntington's disease. The aggregates have a new toxic function in the cells. For the toxic effects within the cells of the English term gain of ( toxic) function is used.

In the English literature, the terms have been established proteinopathy and proteopathy for this form of protein misfolding diseases. The German equivalent terms Proteopathie and Proteinopathie ( the prefix Proteo - =, protein ' and the suffix- pathy = disease ') have, however, been hardly enforced in the German literature.

Currently (as of 2011 ) are known over 100 Proteinopathien in humans and animals. They are caused by the deposition of about 20 non-homologous proteins. A large and important group form the amyloidoses.

The protein misfolding diseases with gain of toxic function include the following diseases:

The protein misfolding disorders also include disorders in which the misfolded proteins are broken down in the proteasome, which do not have sufficient amounts of the protein to the cells or to the organism. This loss of function, engl. loss of ( physiological ) function can lead to diseases such as cystic fibrosis. In most patients with cystic fibrosis F508 mutation is a (type deletion ) in the CFTR protein - a chloride channel - before. The deletion of three nucleotides causes the amino acid phenylalanine is missing at position 508 of the CFTR ( in the one letter F). Due to this mutation is the highly complex CFTR, which has, among other 21 transmembrane protein domains, greatly changed in its folding kinetics. The folding process of the CFTR wild type already required more than two hours, and only about 30 % of the synthesized CFTR molecules folds quickly enough to escape the ER -associated protein degradation ( ERAD ). The F508 - CFTR folding even a little worse and is completely degraded, although it would be fully functional in principle as an ion channel. Affected by this mutation, patients lack the chloride channel ( = loss of function ), which has to follow that the composition of the secretions of various excretory glands change drastically.

A loss of physiological function is inter alia in the following diseases before:

Moreover, there are protein misfolding diseases, in which both a loss of function, as well as the toxic protein deposits can be pathological. An example is the alpha -1-antitrypsin deficiency. A mutation in the SERPINA1 gene for the acute-phase protein α -1 - antitrypsin, - a protease inhibitor - encoding causes misfolding of α -1 -antitrypsin. α -1-antitrypsin is expressed mainly in the liver by hepatocytes. Because of misfolding, it can not be secreted from the hepatocytes and forms intracellular deposits. The loss of function in the affected patients leads to a progressive pulmonary emphysema, as by the lack of α -1 -antitrypsin, the enzyme leukocyte elastase ( human leukocyte elastase german, HLE ) can unrestrained destroy the lung structure. The deposits of α -1 -antitrypsin in the hepatocytes leading to emphysema parallel to cirrhosis.

Treatment concepts

The protein misfolding diseases are currently incurable. For the most common neurodegenerative diseases that are caused by a gain of toxic function, there is no causal or curative therapies. The treatment of patients is usually symptomatic or purely palliative. There are some future curative treatment approaches, such as gene therapy, but these are removed by an authorization for many years.

Protein misfolding diseases that are caused by a loss of function of the protein, are partly curatively treatable. In enzyme replacement therapy to the patient, the missing protein, which is produced by genetic engineering, artificial fed by infusion. Chaperon therapies may be future treatment options for both types of protein misfolding diseases. Molecular chaperones are proteins whose main task is to " help " newly synthesized proteins in their correct folding to. In addition, " artificial" chemical and pharmacological chaperones have been identified and developed to assist the folding process also. The drug sapropterin treatment of phenylketonuria is an example of an approved pharmacological chaperone. The iminosugars 1- deoxygalactonojirimycin ( DGJ ), an international non-proprietary name Migalastat is another pharmacological chaperone, which is currently (as of October 2011) in Phase III clinical trials to test the efficacy in patients with Fabry disease is.

The occurring mainly in green tea, epigallocatechin gallate (EGCG ) is obviously to assist in the location, the correct folding of proteins. In in vitro experiments, EGCG could inhibit fibrillogenesis ( fibril formation ) of huntingtin, α -synuclein and β -amyloid. EGCG ensures that instead of the fiber-like fibrils originate toxic hazardous spherical oligomers. Obviously, it is to dissolve already formed plaques in the situation. In mice, the color plaque burden in the cortex, hippocampus and in the entorhinal cortex was reduced by approximately 50 %.

Proteopathy

Biochemical mechanism

Causes

Gain -of -toxic -function

Treatment concepts

Further Reading