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Misfolded Proteins in Alzheimer's and Parkinson's Diseases

Linda Crampton is an experienced teacher with a first-class honors degree in biology. She writes about the scientific basis of disease.

Proteins can't function unless they are folded properly. On the left is an unfolded protein made of a chain of amino acids and on the right is the final folded state of the protein.

Proteins can't function unless they are folded properly. On the left is an unfolded protein made of a chain of amino acids and on the right is the final folded state of the protein.

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 (also known as ALS and Lou Gherig's disease), 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. Pharmacoperones may one day be useful for treating human diseases.

Levels of Protein Structure

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.

An Important Note

The disease information in this article is given for general interest. If people have questions about one of the diseases with respect to themselves or a loved one, they should consult a doctor.

Misfolding of Proteins and Potential Problems

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. A gene contains the code for obtaining amino acids and placing them in a specific order in a particular 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.

A protein tangle and a damaged neuron in Alzheimer’s disease

A protein tangle and a damaged neuron in Alzheimer’s disease

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 fatal, though some people who have the disease live for many years after a diagnosis.

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 proteins misfold. 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 bodies in the substantia nigra of the brain; the bodies are made of alpha-synuclein fibrils

Lewy bodies in the substantia nigra of the brain; the bodies are made of alpha-synuclein fibrils

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 (if it appears at all) 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 some 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.

At least one pharmacoperone works in mice.

At least one pharmacoperone works in mice.

It's important to note that pharmacoperone benefits have been found in isolated cells and in mice but haven't been explored in the human body. Mouse research often applies to humans, but this is not always the case.

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 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 without harming us in any way. 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.

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. As one of the articles referenced below states, pharmacoperone experiments are still in the preclinical stage. Future discoveries may be exciting and very useful, however. 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
  • New drug approach could lead to cures for wide range of diseases from the Medical Xpress news service
  • Pharmacoperones and disease treatment (abstract) from the NIH or the National Institutes of Health
  • An assessment of pharmacoperone drugs from Taylor & Francis (abstract)
  • The effects of a pharmacoperone on proteins associated with Alzheimer's disease in mice from Temple University and TrialSite News
  • Pharmacoperones as novel therapeutics from the American Physiological Society

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.

© 2013 Linda Crampton


Linda Crampton (author) from British Columbia, Canada on January 13, 2014:

Thank you very much for the comment, RTalloni. Yes, it does seem that we are close to major breakthroughs for some health problems. I hope these breakthroughs happen very soon!

RTalloni on January 13, 2014:

Thanks so much for putting this easy to follow post together for HubPages. This is easy to follow and interesting. Sometimes it seems that we really are on the verge of breakthroughs for some diseases.

Linda Crampton (author) from British Columbia, Canada on January 09, 2014:

I am so sorry about your sister's condition, Dianna. I hope very much that new treatments that will help her are discovered very soon. It's important that scientists understand the role of misfolded proteins in disease and discover the ways to correct the misfolding as soon as possible. Thank you very much for the visit.

Dianna Mendez on January 09, 2014:

I have a sister who is in the early stages of Alzheimer's disease and it is interesting to know how this disease forms. I only hope and pray that the future will provide us answers to these types of illness.

Linda Crampton (author) from British Columbia, Canada on December 30, 2013:

I hope that pharmacoperones prove to be useful and that the diseases are cured within our lifetime, too, Deb. Thanks for the visit.

Deb Hirt from Stillwater, OK on December 30, 2013:

Such terrible diseases due to these misfiled proteins. I hope these things can be cured sometime in our lifetime. Go pharmacoperones!

Linda Crampton (author) from British Columbia, Canada on December 28, 2013:

Thank you very much for the comment and the vote, drbj. Pharmacoperones are definitely exciting chemicals!

drbj and sherry from south Florida on December 28, 2013:

Pharmacoperones could be the clue to curing and eradicating many diseases now prevalent in our world. Let's hope so. Thanks for this informative and exciting introduction, Alicia, to this subject. Voted up, m'dear.

Linda Crampton (author) from British Columbia, Canada on December 27, 2013:

Thanks for the visit, Heidi. I hope that our knowledge of these diseases increases, too. It would be absolutely wonderful to eventually eliminate them!

Heidi Thorne from Chicago Area on December 27, 2013:

I do hope that our understanding of the basis of these devastating diseases can continue to expand, leading to eliminating them from our population. Thanks for sharing these exciting developments!

Linda Crampton (author) from British Columbia, Canada on December 27, 2013:

Hi, Bill. I hope very much that the research leads to breakthrough treatments, too. The discovery of pharmacoperones is certainly exciting!

I did have a nice Christmas, thank you. I hope your Christmas was enjoyable and that you have a great 2014.

Bill De Giulio from Massachusetts on December 27, 2013:

Hi Linda. This is fascinating and exciting information. We have a friend who died of CJD (Prion Disease) and I wouldn't wish that on my worst enemy. Let's hope this leads to a breakthrough.

Hope you had a nice Christmas.

Linda Crampton (author) from British Columbia, Canada on December 26, 2013:

Thank you for the comment, Martie! I appreciate it. I'm hoping very much that the solution to protein misfolding will also be the solution to some serious diseases.

Martie Coetser from South Africa on December 26, 2013:

Interesting! Indeed excellent research and discovery of yet another treatment that may bring an end to serious, heartbreaking diseases. Thanks, Alicia :)

Linda Crampton (author) from British Columbia, Canada on December 26, 2013:

Hi, WriterJanis. I agree - science is amazing! Thanks for the visit.

Janis from California on December 26, 2013:

That's a positive step that they were able cure mice. Amazing what science can achieve.

Linda Crampton (author) from British Columbia, Canada on December 26, 2013:

Hi, Molly Meadows. Yes, it would be wonderful if this research could lead to a cure for serious diseases such as ALS. ALS is a disease that interests me very much, since my mother died from it. I find it fascinating that human diseases that seem so different could actually be caused by a similar mechanism!

Molly Meadows on December 26, 2013:

Thank you for this hopeful information. How wonderful if this could be the beginning of a cure for Parkinson's or ALS!

Linda Crampton (author) from British Columbia, Canada on December 25, 2013:

Thanks for the visit, Faith. I appreciate your votes and the share, as I always do! I hope you're having a wonderful Christmas.

Faith Reaper from southern USA on December 25, 2013:

You always educate us on important scientific research! Interesting and insightful hub.

Up and more and sharing

Merry Christmas to you and yours,

Faith Reaper

Linda Crampton (author) from British Columbia, Canada on December 23, 2013:

Thank you, Bill. I hope that you and Bev have a wonderful Christmas!

Bill Holland from Olympia, WA on December 23, 2013:

The future should indeed be exciting. Excellent information as always my friend. Merry Christmas to you and yours.