Protein misfolding disease

from Wikipedia, the free encyclopedia

As protein misfolding diseases , including protein folding diseases ( Engl. Protein misfolding diseases or protein misfolding disorders or conformational diseases or proteopathies called), it refers to those diseases caused by incorrectly folded proteins caused inside and outside of cells. The misfolded proteins are either stored in the cells or broken down in the proteasome . In the first case, toxic deposits (plaques) are formed, in the second there is a loss of function due to a deficiency of the corresponding protein in the cell or in the entire organism . Both can become pathological for the person concerned over time and, depending on the protein concerned, lead to different diseases.

Biochemical mechanism

Schematic representation of protein quality control in the endoplasmic reticulum.
The linear, unfolded protein introduced into the ER via a transport protein begins to fold with the help of chaperones (not shown). If it is recognized as correctly folded by the protein quality control, it is removed from the ER via a vesicle. Misfolded proteins are smuggled into the cytosol via a transport protein and broken down into fragments in a proteasome. Amorphous aggregates can also be broken down by autophagocytosis .
If too many molecules are broken down due to incorrect folding, this can lead to a loss of function in the cell or the entire organism. If too many insoluble, no longer degradable aggregates are formed, deposits are toxic for the cell and the entire organism.

In most cells of all organisms , a wide variety of proteins are constantly produced in the course of protein synthesis, which fulfill a wide variety of functions in the cell and in the entire organism. For a protein to function correctly, its tertiary structure is of crucial importance. This structure is achieved through a process called protein folding. Protein folding is a complex and delicate process. Correct protein folding is monitored by the protein quality control. Statistically, around 30% of all proteins from protein biosynthesis are incorrectly folded and are normally broken down in the cell's proteasome within around ten minutes. The accumulation of incorrectly folded proteins in the endoplasmic reticulum leads to the unfolded protein response , a stress response of the cells that is associated with a suppression of translation and an increased synthesis of chaperones .

A single misfolded protein molecule is not responsible for the serious clinical pictures of protein misfolding diseases. To do this, large quantities of these proteins must be produced or the number of correctly folded molecules must be reduced. In the case of prions , this happens because a misfolded molecule on contact with a correctly folded molecule causes the correct one to unfold and ultimately incorrectly fold again. Since the first incorrectly folded protein is not changed by this process (it functions as an enzyme ), two incorrectly folded molecules are then present. These can fold further correct molecules.

The defective proteins are also called defective ribosomal products ( Engl. Defective ribosomal products , drips), respectively.

causes

The reasons for incorrect protein folding are complex. Gene mutations in exons that lead to changes in the amino acid sequence , i.e. the primary structure of the gene product , have a direct influence on the secondary and tertiary structure, or on the protein folding kinetics. Errors in transcription or translation can also lead to misfolding of the proteins. Another possible factor is the environment; In infectious prion diseases , for example, the prion protein is ingested with food or transferred using surgical instruments. There are now first indications of a toxin (BMAA) produced by cycads and cyanobacteria , which, when incorporated into proteins, leads to their misfolding and thus possibly to a form of ALS.

Gain-of-toxic function

Fine tissue section with Alzheimer's plaques
α-Synuclein staining of a Lewy body in the substantia nigra in Parkinson's disease.

If the DRiPs cannot be broken down in the proteasome, for example because they have previously aggregated to form aggregates, 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. The English term gain of (toxic) function is used for the toxic effect within the cells .

In the English-language specialist literature, the terms proteinopathy and proteopathy have become established for this form of protein misfolding disease . The corresponding German terms proteopathy and proteinopathy (the prefix proteo- = ' protein ' and the suffix -pathie = 'disease'), on the other hand, have barely established themselves in the German-language specialist literature.

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

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

illness causative protein Remarks
Alzheimer's disease β-amyloid , tau Type tauopathy
Pick disease dew Type tauopathy
Corticobasal degeneration dew Type tauopathy
Silver grain disease dew Type tauopathy
Progressive supranuclear palsy dew Type tauopathy
Parkinson's Disease α-synuclein Synucleinopathy type
Multiple system atrophy α-synuclein Synucleinopathy type
Lewy body dementia α-synuclein Synucleinopathy type
Chorea huntington Huntingtin Polyglutamine ( polyQ expansion disease ) from the family of trinucleotide repeat disorder
Spinocerebellar ataxia u. a. Ataxin-2 Polyglutamine disease
Kennedy type spinobulbar muscular atrophy Androgen receptor Polyglutamine disease
Dentatorubro-Pallidoluysic Atrophy (DRPLA) Atrophin Polyglutamine disease
ATTR amyloidosis and AP amyloidosis Transthyretin Amyloidosis
hereditary systemic amyloidosis (mostly) transthyretin Amyloidosis
non-hereditary systemic amyloidosis Immunoglobulin light chains (AL type), APP fragments (AA type), β2-microglobulin (AB type) Amyloidosis
Transmissible spongiform encephalopathies Prions Prion diseases and the like a. Creutzfeldt-Jakob disease , fatal familial insomnia , Gerstmann-Sträussler-Scheinker syndrome , Kuru
Cataract (cataract) multiple proteins Denaturation of various lens proteins
Amyotrophic lateral sclerosis (at least in some variants of the disease) TDP-43, FUS, SOD1
Alexander disease Glial Fiber Acid Protein (GFAP)
CADASIL Notch 3
Sickle cell anemia hemoglobin
Frontotemporal Flap Degeneration (FTLD-TLP) TDP-43
Alveolar proteinosis Surfactant Protein-C
Sporadic inclusion body myositis β-amyloid (not yet established)
Type 2 diabetes mellitus Amylin

Loss-of-physiological-function

Protein misfolding diseases also include diseases in which the misfolded proteins are broken down in the proteasome, as a result of which insufficient quantities of the protein are available to the cells or the organism. This loss of function, engl. loss of (physiological) function , can lead to diseases such as cystic fibrosis . Most patients with cystic fibrosis have a ΔF508 mutation ( deletion type ) in the CFTR protein - a chloride channel . The deletion of three nucleotides causes the amino acid phenylalanine (in the one -letter code F) to be missing at position 508 of CFTR . This mutation greatly changes the folding kinetics of the highly complex CFTR, which has 21 transmembrane protein domains , among other things . The folding process of the CFTR wild type takes more than two hours and only about 30% of the synthesized CFTR molecules fold fast enough to escape ER-associated protein degradation (ERAD). The ΔF508-CFTR folds even more poorly and is completely broken down, although in principle it would be fully functional as an ion channel. The patients affected by this mutation lack the chloride channel (= loss of function), which means that the composition of the secretions of various excretory glands is drastically changed.

A loss of physiological function occurs in the following diseases, among others:

illness defective protein / gene Remarks
Cystic kidneys Polycystin-1
Charcot-Marie-Tooth disease Aminoacyl-tRNA Synthetase (AARS)
X-linked lymphoproliferative syndrome SH2D1A
Hirschsprung's disease Receptor Tyrosine Kinase Ret
Homocystinuria and methylmalonic aciduria MMACHC
Patellar hypoplasia TBX4
Sclerosteosis Sclerostin
Cystic fibrosis CFTR
Phenylketonuria Phenylalanine hydroxylase
Hand-foot-genital syndrome Homeobox protein A13
lysosomal storage diseases various lysosomal enzymes over 40 individual diseases, u. a. Gaucher's disease , Fabry 's disease , Tay-Sachs syndrome, or Krabbe's disease
QT syndrome u. a. hERG
Angelman Syndrome UBE3A
hereditary breast cancer BRCA1

Gain-of-function and loss-of-function

In addition, there are protein misfolding diseases in which both a loss of function and the toxic protein deposits can become pathological. An example of this is alpha-1 antitrypsin deficiency . A mutation in SERPINA1 gene which codes for the acute-phase protein α-1-antitrypsin - a protease inhibitor - encoded , causes misfolding of α-1-antitrypsin. α-1-antitrypsin is mainly expressed by hepatocytes in the liver . Because of the misfolding, it cannot be secreted by the heptocytes and it forms intracellular deposits. The loss of function leads to progressive pulmonary emphysema in the affected patient , as the lack of α-1-antitrypsin means that the enzyme leukocyte elastase ( human leukocyte elastase , HLE) can destroy the lung structure unchecked. The deposits of α-1-antitrypsin in the hepatocytes lead to liver cirrhosis parallel to the pulmonary emphysema .

Treatment concepts

Saproterin, a pharmacological chaperone
Epigallocatechin gallate, a component of green tea, supports the protein folding process

The protein misfolding diseases are currently not curable. There is as yet no causal or curative therapy for the most common neurodegenerative diseases caused by a gain of toxic function . Treatment of the patients is usually symptomatic or purely palliative . There are some future curative treatment concepts, such as gene therapy , which are still many years away from approval .

Protein misfolding diseases, which are caused by a loss of protein function, can in some cases be treated curatively. In enzyme replacement therapy , the missing protein, which is genetically engineered, is artificially infused into the patient . Chaperone therapies may be future treatment options for both types of protein misfolding disorders. Molecular chaperones are proteins whose most important task is to “help” newly synthesized proteins with their correct folding. In addition, “artificial” chemical and pharmacological chaperones were identified and developed that also support the folding process. The active ingredient sapropterin for the treatment of phenylketonuria is an example of an approved pharmacological chaperone. The imino sugar 1-deoxygalactonojirimycin (DGJ), international non- proprietary name Migalastat, is another pharmacological chaperone that is currently (as of October 2011) in clinical phase III for testing its effectiveness in patients with Fabry disease.

The especially green tea occurring epigallocatechin gallate (EGCG) is obviously to support able to correct folding of proteins. In in vitro experiments , EGCG was able to inhibit fibrillogenesis (the formation of fibrils ) of huntingtin, α-synuclein and β-amyloid. EGCG ensures that harmless spherical oligomers are formed instead of fibrous toxic fibrils . Obviously, it is also able to dissolve plaques that have already formed. In colored mice , the plaque load in the cortex, hippocampus and in the entorhinal cortex could each be reduced by about 50%.

Misfolding outside of cells

Since around 2008, it has been increasingly recognized that protein misfoldings not only lead to problems within cells, but also to a significant extent in the interstitial space . The importance of the glyphatic system (waste disposal of the central nervous system ) for the removal of misfolded proteins from the brain was discovered in 2012 and has been the subject of intensive research ever since. This applies in particular to all of the known and widespread neurodegenerative diseases .

further reading

Reference books

Review article

Individual evidence

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