Misfolded Proteins in Alzheimer's and Parkinson's Diseases
Protein Misfolding and Disease
Proteins are complex, folded molecules with vital functions in our bodies. The folds aren't random and give the molecule a specific shape and function. Misfolded proteins are involved in some serious human diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, cystic fibrosis, and inherited cataracts. They have also been implicated in type 2 diabetes, amyotrophic lateral sclerosis (ALS), and certain types of cancer.
There are two problems with misfolded proteins in a cell: the fact that their shape has changed and the fact that the cell sends them to the wrong location. Researchers working with mice have found that a group of chemicals called pharmacoperones repair misfolded proteins and enable the cell to transport them to their correct location. More importantly, the researchers have found that one disease caused by misfolded proteins in mice can be cured by a pharmacoperone.
A protein molecule has multiple levels of structure.
- The primary structure of a protein consists of a chain of amino acid molecules. The amino acids are joined together by peptide bonds. The primary structure is sometimes likened to a string of beads on a necklace.
- The secondary structure is formed by the folding of the primary structure into a new shape, such as a helix or a pleated sheet. As in the other levels of protein structure, the folds are held in place by chemical bonds between different parts of the structure.
- The tertiary structure is produced when the secondary structure folds into yet another shape, such as a globular structure.
- Some proteins consist of more than one amino acid chain (or polypeptide). The arrangement of these polypeptides with respect to each other is known as the quaternary structure of the protein.
Misfolding of Proteins
Since proteins are involved in a multitude of processes in the human body, misfolding is potentially harmful. The chemicals often fold correctly, but this isn’t always the case. A variety of environmental factors surrounding a protein can affect its final shape. These factors include the local pH and temperature and the chemical composition of proteins located close to the one being folded. Gene mutations can also affect folding by changing the structure of a protein.
In young people or in healthy cells, altered and misfolded proteins are often broken down and removed by the cell and no damage is done. In older people or in people with certain genetic problems, the number of misfolded proteins may overwhelm the cell's ability to remove them. Under these conditions, the damaged molecules tend to clump together.
In the 1990s, scientists realized that protein misfolding can not only stop the molecule from working but also contribute to disease. It was exciting to discover that a similar mechanism was behind a range of apparently unrelated diseases. This could mean that a therapeutic approach aimed at correcting or compensating for misfolded proteins might be useful in all of the illnesses.
Dementia is a set of symptoms that includes memory loss and difficulty in solving problems and making judgements. Several diseases can cause dementia, including Alzheimer's disease and some cases of Parkinson's disease.
Alzheimer's Disease, Beta-Amyloid, and Tau Protein
Alzheimer's disease is the most common cause of dementia. It's a very unpleasant neurodegenerative condition. An affected person gradually develops severe memory loss, difficulty in solving problems and making decisions, confusion, and major changes in personality and behaviour.
The disease is characterized by tangles of misfolded beta-amyloid proteins (or more accurately, protein fragments) in the brain. These tangles form around the nerve cells, or neurons, and are known as plaques. A second brain protein called tau also becomes misfolded and tangled during Alzheimer's disease. Tau tangles form inside the neurons.
The misfolded proteins have altered properties and can't function properly. Brain neurons die and the patient develops progressive memory loss and behaviour problems. At the moment, Alzheimer's disease is always fatal.
For some time it wasn't clear whether the misfolded proteins in the brain were the cause of Alzheimer's disease or a consequence of the disease. Now there is enough evidence for researchers to conclude that the altered proteins are most likely the cause of Alzheimer's. A major question that is still bring investigated is why the misfolded proteins develop. Another question that needs to be answered is which of the two protein deposits is responsible—or most responsible—for the disease. At least some researchers currently think that the tau tangles are more important.
Misfolded Proteins in Alzheimer's Disease
Parkinson's Disease, Lewy Bodies, and Alpha-Synuclein
Parkinson's disease is another neurodegenerative condition. In this illness, dopamine-secreting cells in a part of the brain called the substantia nigra die and the patient develops movement problems. Dopamine is a neurotransmitter, which is a chemical that transmits a signal from one neuron to another.
Another feature of Parkinson's disease is the appearance of small clumps of misfolded proteins inside neurons in the substantia nigra. The clumps are known as Lewy bodies and are made of a protein called alpha-synuclein.
As in Alzheimer's disease, the misfolding causes the altered proteins in the brain to aggregate. Also as in Alzheimer's disease, there has been debate about whether the Lewy bodies cause the death of the dopamine-secreting cells or form as a result of this death.
In an interesting experiment at the University of Pennsylvania, researchers injected misfolded alpha-synuclein into the brain of healthy mice. The injection caused Lewy bodies to form, dopamine-producing cells to die, and typical symptoms of Parkinson's disease to appear, adding support to the idea that misfolded proteins are the cause of Parkinson's disease.
Lewy Body Dementia
Not all patients with Parkinson's disease develop dementia, but some do. The condition is known as Parkinson's disease dementia. Lewy bodies also appear in a condition known as Lewy body dementia (which is called dementia with Lewy bodies in some classification systems).
In Parkinson's disease, the Lewy bodies are found mainly in the substantia nigra in the midbrain. In Lewy body dementia, they are mostly spread through the cerebral cortex, or the surface layer of the brain. Dementia develops later in a person with Parkinson's disease than in a person with Lewy body dementia.
The two disorders described above are closely related to each other and may be different forms of the same disease. Patients with either disease eventually develop similar symptoms. The evidence obtained so far indicates that the changes in their brains become more similar as well.
Confusingly, the names for alpha-synuclein diseases vary. For example, some sources classify both Parkinson's disease with dementia and dementia with Lewy bodies as types of Lewy body dementia.
Living With Parkinson's Disease
What Are Pharmacoperones?
A pharmacoperone is a medicinal drug. It's a small molecule that enters a cell and binds to a misfolded protein. The pharmacoperone corrects the misfolding and enables the protein to do its job.
Cells have a quality control system. When this system detects a misfolded protein, it sends the protein to the wrong part of the cell. This means that even if the misfolding doesn't interfere with the protein's function, the protein is still unable do its job.
The word "pharmacoperone" is a contraction of "pharmacological chaperone". A pharmacoperone corrects the dual problems of misfolding and misrouting of proteins. It has a specific structure that enables it to join to the target protein and promote its transport to the correct area. It's thought that the pharmacoperone acts as a template for the right shape of the protein. Once the chemical has folded correctly, the protein passes through the cell's quality control system successfully and is able to do its job.
Pharmacoperones and Human Disease
Pharmacoperones have previously been shown to correct protein problems in isolated cells. An experiment involving mice showed that one kind is effective inside a living body. The researchers were able to cure mice of a disease that causes sterility in males by administering a specific pharmacoperone.
The fact that a pharmacoperone has successfully treated an illness in mice is a very hopeful sign for the future. It doesn't mean that a cure for human diseases is imminent, however. Clinical tests are needed to see if the molecules work in humans. In addition, it will take time to screen potential drugs to see if they can correct the misfolding of specific proteins in our body. This is probably the process that will delay the use of pharmacoperones in medicine. Finding the dose that is effective yet safe will also take time. Still, the molecules are promising and could be extremely useful in the future.
It's important to note that pharmacoperone research has been done in isolated cells and in mice but not (as far as I know) in the human body. Mouse research often applies to humans, but this is not always true.
Preventing or Correcting Protein Misfolding
Ideally, it would be nice to correct the cause of a disease. The instructions for making a protein are encoded in a gene. If the gene is mutated (altered), it will code for a mutant protein. Replacing a mutant gene with a normal one might be the best treatment for a disease caused by a misfolded protein. If this can't be done or isn’t applicable, however, correcting the misfolding is important. A patient may have to take pharmacoperones for their entire life in order to compensate for the production of misfolded proteins in their body.
The research that is being performed in relation to the complex topics of protein folding, misfolding, and disease may produce other disease treatments in addition to pharmacoperones. The research is intensifying as scientists discover the widespread effects of misfolded molecules. Future discoveries may be exciting and very useful. I hope this is the case.
Beta-amyloid and tau protein in Alzheimer's disease from the AAAS (American Association for the Advancement of Science)
Lewy body information from the American Parkinson Disease Association
Lewy body formation in mice from Pennsylvania State University
Oregon Health & Science University. (2013, December 9). New drug approach could lead to cures for wide range of diseases. ScienceDaily. Retrieved February 26, 2019 from www.sciencedaily.com/releases/2013/12/131209181101.htm
Pharmacoperones and disease treatment from the NIH (National Institutes of Health)
A recent assessment of pharmacoperone drugs from Taylor & Francis (abstract)
This content is accurate and true to the best of the author’s knowledge and does not substitute for diagnosis, prognosis, treatment, prescription, and/or dietary advice from a licensed health professional. Drugs, supplements, and natural remedies may have dangerous side effects. If pregnant or nursing, consult with a qualified provider on an individual basis. Seek immediate help if you are experiencing a medical emergency.
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© 2013 Linda Crampton