Surprising Role of Prions in Neurodegenerative Diseases
April 24, 2014
Prions are infectious agents, but of a very unusual kind. Technically, they are just proteins with an incorrectly folded conformation. However, there is a major difference between just any misfolded proteins (which are common in nature) and prions.
A prion, once it enters an organism, serves as a template for converting the normally folded proteins of the same kind into the alternative conformation. The process is self-propagating and results in a chain reaction, leading to conversion of a significant number of normal, functional proteins into an abnormal form. This new structure is usually extremely stable and tends to accumulate in the form of various insoluble agglomerates. This can have various negative consequences, depending on the nature of a particular prion.
The idea that an infectious agent might contain no genetic material in the form of DNA or RNA remained, for very long time, a controversial and hotly debated topic. Much of the publicity associated with prions came from the fact that the first (and so far the only) prion-transferred human infectious disease, kuru, was found among several tribes in Papua New Guinea and was clearly linked to the cannibalistic rituals. Kuru turned out to be closely related to the rare Creutzfeldt-Jakob Disease (CJD) and most likely originated from a sporadic case of this disease in early 1900s. Persistent failure to find any usual infectious agents led to the speculations that disease is transferred by proteins. This hypothesis was eventually confirmed with identification and characterization of the specific prion capable of self-proliferation by changing the conformation of normal cellular proteins of the same sequence.
The ability of prions to change the conformation of normal proteins means that, in the absence of counteracting processes, it would be enough to “seed” the environment with a prion to eventually cause the conversion of all available prion precursors into prions. This is exactly what happens in kuru, as well as in bovine spongiform encephalopathy (better known as BSE or “mad cow” disease) that can cross the species boundary and infect humans.
For very long time, the existence of prions and associated conditions was treated as a scientific curiosity with very little significance to broader health issues. This has changed dramatically in the last few years. It turned out that prions and prion-like molecules are extremely relevant to some of the most common neurodegenerative disorders among humans.
Prions have offered surprising and unexpected explanations to the development of such conditions as Alzheimer’s disease, Parkinson’s disease, motor neuron disease and many related syndromes. Thanks to this new understanding of the role of prion-like proteins, a profound change in the way we think about the nature of neurodegenerative diseases has taken place in the recent years.
Although prion-like molecules in human brain disorders do not act as infectious agents, they are capable of freely moving from one neuron to another and thus propagating through the neuronal networks – eventually affecting vast areas of brain. The initial formation and consequent propagation of prions can be helped by certain genetic alterations, which are linked to the earlier onset of the diseases.
Alzheimer’s disease is the most common case of dementia among humans. Brain cells get lost and some regions of cerebral cortex shrink in size as the disease progresses. Classical hallmarks of Alzheimer’s disease – amyloid plaques and neurofibrillary tangles – are typically observed in the brain of patients with this condition.
Amyloid plaques consisting of insoluble agglomerates of beta-amyloid peptide are one of the most obvious features of the disease. Recent research findings demonstrate that the seeds of incorrectly folded beta-amyloid peptides can be transferred from one neuron to another, thus causing progression of the disease.
Neurofibrillary tangles are also observed in Alzheimer’s patients, as well as in multiple tauopathies. Their density and pattern of distribution correlate closely with the stages of disease progression. Neurofibrillary tangles are formed inside the neurons and consist of insoluble twisted fibers of modified protein tau. Normal function of the tau protein is stabilization of microtubules. The latter are key components of cytoskeleton and provide a transportation system inside the cells. They are vital for transporting various molecules between different parts of neuron. Incorrectly folded tau, however, precipitates inside the cell and disrupts the transportation system. Again, like in the case of beta-amyloid, the seeds of misfolded tau proteins can be transferred between neurons.
It seems that acquiring the wrong form of beta-amyloid peptide or tau protein by the cell through one or another mechanism initiates the process of conversion of soluble proteins into insoluble aggregates, leading to damage to the brain functions in general.
In Parkinson’s disease, the most distinctive pathological feature is the formation of so-called Lewy bodies. They consist mostly of protein called alpha-synuclein. Lewy bodies gradually spread from brainstem to forebrain resulting in the progressive loss of various brain functions. Similar to beta-amyloid and tau proteins, alpha-synuclein forms insoluble polymeric agglomerates. The normal function of alpha-synuclein is not fully understood, although it is known to be important for the development of normal cognitive functions. Once a misfolded form of alpha-synuclein is formed, it can spread from one neuron to another, acting as “seeds” that eventually affect most of the interconnected cells.
Motor neuron disease, which is characterized by muscle atrophy, progressive weakness and difficulties in speaking, breathing and swallowing, is caused by degeneration of upper and lower motor neurons. Although the initial cause of motor neuron disease is unknown, the growing evidence points to the self-propagation of two other prion-like misfolded proteins, superoxide dismutase 1 (SOD1) and DNA/RNA-binding protein TDP-43, as major factors in the development and progression of this condition. Both SOD1 and TDP-43 are capable of participating in seeded aggregation, spreading from cell to cell after an initiating event.
It seems that most neurodegenerative conditions involve one or another type of proteins in misfolded alternative conformation that are capable of self-propagation by changing conformations of normally folded native analogues.
These prion-like misfolded conformations are capable to self-aggregation into various insoluble polymeric complexes clearly visible in or around the affected brain cells. The self-propagation of misfolded proteins depletes the cellular stock of normally folded proteins and therefore must, in one way or another, affect the normal functions of the cells. The accumulation of agglomerates themselves can also have detrimental effect on the cell functioning.
In most cases, the nature of the initial event that leads to misfolding of proteins and formation of seeds remains obscure. It is clear that genetic alterations play a role in only around 10 per cent of all neurodegenerative diseases. Sporadic cases may be initiated by various events which may include environmental factors, trauma, or other diseases. The incidence of these conditions increases with the age, thus indicating that cellular events associated with aging play a central role in the initiating process.
The mechanism of how prions spread from one neuron to another remains insufficiently studied. A number of possibilities are discussed in the literature but definite proofs still need to materialize. It appears that prion-like molecules spread via neuronal pathways using the existing connections between cells. As a result, the location of initial event dictates the pattern of disease spreading that happens at later stages.
The absence of adequate treatments for neurodegenerative diseases is tragic. Despite many decades of research, no drugs with even moderate positive effects have so far been introduced. Arguably, the reason for the lack of treatment lies in the fact that researchers have tried to use the wrong targets in previous drug development programs. Considering our new findings about the role of prions, many previous attempts to develop treatments seem ill-positioned.
Our new understanding about the role of prions points to novel therapeutic approaches. They include pharmaceutical interventions aimed at lowering the level of prion precursor protein, inhibiting prion formation, or accelerating the clearance of prions.
Lots of questions related to the development of neurodegenerative diseases still remain unanswered. However, the prion theory provides much needed clarity in our understanding of these diseases’ progression. Clear understanding of the importance of prion-like proteins in the mechanisms and development of various brain disorders have allowed us, for the first time, to have a clearer view on how to develop effective drugs.
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