One Ring to Rule Them All: Cure-all Drug for Neurodegenerative Conditions Possible

The secret to finding a single drug treatment for neurodegenerative conditions may lie in unfolding the mystery of misfolded proteins. Most of the non-infectious neurodegenerative diseases (like Alzheimer’s and Parkinson’s) are characterized by progressive death of neurons due to the accumulation of misfolded proteins in brain cells.

To understand the pathogenesis of these diseases we have to first understand proteins.  They are essential for building our body structures and functional regulation. Thus, there are thousands of different proteins with various functions. These proteins are made up of only 20 amino acids. These 20 amino acids are like the alphabet in a language, they can create thousands or millions of proteins when used in different combinations. A single misplaced letter in a word results in a spelling error. Similarly, a misplaced amino acid can create the wrong kind of protein. Misplaced words can create a grammatically wrong and incomprehensible sentence. In a similar fashion, misfolded proteins have no structural or functional value.

Another important concept that has to be understood is how prions are involved. From school books, we know that infections are caused by microorganisms like bacteria, fungi, and viruses. All of them have genetic material in the form of nucleic acids (as DNA or RNA, or both), that is essential for the reproduction or multiplication of these microorganisms. But prions, unlike microorganisms, are just protein chains that are infectious. These proteins, after entering the living organism, cause misfolding of proteinaceous infectious particles (PrPs). PrPs are found in all of us, our brain and neurons are especially rich in them. Their role, however, is still poorly understood.

Misfolded PrPs cause encephalopathies. These misfolded proteins are also thought to cause a chain reaction resulting in the misfolding of other proteins. These misfolded proteins propagate further like an infectious microorganism. What causes this chain reaction and propagation is still unclear. These chains of proteins are called prions. They cause Creutzfeldt-Jakob disease (CJD) in humans and bovine spongiform encephalopathy (BSE) in cattle. Prions have a long incubation period, it takes a long time for the disease to appear and progress.

In many neurodegenerative diseases like Alzheimer’s and Parkinson’s, misfolded proteins get progressively accumulated in brain cells, leading to the death of neurons. There is growing evidence that the prion-like process of seeding and templated protein corruption are behind the progression of these diseases.

PrP (healthy prion) is commonly found in our brain cells. However, when a defective prion protein is somehow introduced into the cells, it causes misfolding of newly forming PrP. This process is progressive and propagated like an infectious disease to the other cells. Thus, one of the potential treatment approaches is to block the propagation of this prion-like protein.

Accumulation of these prion-like misfolded, mutant proteins is toxic for cells. The prolonged toxic stress produced in brain cells induces specific death pathways. Understanding how these toxic proteins cause stress for neurons and why the cells die could also help to find new treatment strategies.

With increasing evidence that prion-like mechanisms are behind the progression and propagation of most neurodegenerative disorders, scientists have started looking for methods to stop this propagation. One such method is the use of specific immunotherapy, where researchers are trying to develop vaccines that can cure these disorders, or at least stop disease progression.

Larger proteins in our body contain hundreds or thousands of amino acids in various combinations. These large proteins are folded into specific structures. If a protein is misfolded, it loses its specific structure too. It also loses its properties and becomes toxic for cells. One therapeutic approach aims to develop a vaccine that can activate our immune system (B and T cells) against these defective misfolded proteins so that they are destroyed in a timely manner.

To achieve this aim, scientist have tried two methods. One of them is to create a vaccine that works against very short chains of misfolded proteins called monomers. They exist while these proteins are being assembled. Another approach is to target the fully formed misfolded protein fibrils. However, both of these methods have so far failed to produce the intended results.

Recently, researchers are exploring a new strategy for the development of immunotherapy against these diseases. This strategy targets so-called “oligomers”. The oligomers are molecular intermediates that exist in the process of assembling the prion fibrils. They are not very small like monomers (initial building blocks of prions) and are also not fully formed prion fibrils.

Smaller monomers lack the antigenic properties (associated with protein structures called beta-sheets) of misfolded proteins that are needed for an immune response. Meanwhile, fully formed fibrils are too big to propagate through cell walls. Thus, it is quite possible that these oligomers play a critical role in the disease propagation processes. A vaccine or immunotherapy targeting these oligomers could be more effective in initiating an immune response against the misfolded pathological prions than their smaller or larger counterparts. Moreover, these intermediate oligomers are common to most neurodegenerative disorders, unlike fully formed fibrils that are specific to each disease.

Although this new approach has shown some success in animal models, there are several challenges to using such immunotherapy in humans. In humans, it is not easy to initiate the immune response because of “self-tolerance.” The misfolded proteins are very similar to normal proteins (normal PrPs). Even if this immune tolerance can be overcome, there is a risk of initiating the wrong kind of immune response against normal proteins. This may lead to sterile encephalopathy or another kind of damage. Further, the blood-brain barrier also poses a challenge: it is important that antibodies created by a vaccine are able to reach a good concentration in the brain.

Despite these challenges, the idea of having just a single approach to treat all (or at least most) types of neurodegeneration is clearly exciting. These diseases have lots in common in terms of the molecular mechanisms involved, and it is quite likely that immunotherapy targeting all of them can be developed.

References

Frost, B., Diamond, M.I., 2010. Prion-like Mechanisms in Neurodegenerative Diseases. Nat. Rev. Neurosci. 11, 155–159. doi:10.1038/nrn2786

Goedert, M., Clavaguera, F., Tolnay, M., 2010. The propagation of prion-like protein inclusions in neurodegenerative diseases. Trends Neurosci. 33, 317–325. doi:10.1016/j.tins.2010.04.003

Marciniuk, K., Taschuk, R., Napper, S., 2013. Evidence for Prion-Like Mechanisms in Several Neurodegenerative Diseases: Potential Implications for Immunotherapy. J. Immunol. Res. doi:10.1155/2013/473706

Rao, R.V., Bredesen, D.E., 2004. Misfolded proteins, endoplasmic reticulum stress and neurodegeneration. Curr. Opin. Cell Biol. 16, 653–662. doi:10.1016/j.ceb.2004.09.012

Walker, L.C., Diamond, M.I., Duff, K.E., Hyman, B.T., 2013. Mechanisms of Protein Seeding in Neurodegenerative Diseases. JAMA Neurol. 70, 304–310. doi:10.1001/jamaneurol.2013.1453

Image via frolicsomepl/Pixabay.


Source: Brain Blogger

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