Prion diseases are characterised by a pathological conformation of the Prion Protein (PrP). The infectious conformation, called PrPSc (PrP scrapies), is resistant to protease degradation and heat. PrPSc has the unique property of being able to bind to normal PrP and causing it to adopt the pathological conformation in a process known as “templated conversion”. The mutate Prion proteins then acts as a seed from which large protein aggregates are formed. These aggregates are toxic to neurons leading to neurodegeneration[1].
Prion diseases can be sporadic, inherited or acquired. They affect both humans and non-human mammals. For example, bovine spongiform encephalopathy, or mad cow disease, is a prion disease affecting cows, while Creutzfeldt-Jakob is a prion disease affecting humans[2]. The infectious prion particle is able to cross the species barrier, allowing the mad cow disease to be transmitted from cows to humans. Recently, researchers have found evidence for a contentious theory that many neurological diseases including Alzheimer’s disease, Parkinson’s disease and frontotemporal dementia, which do not involve Prion Protein, may propagate within an individual in a prion-like mechanism[3]. Currently, there is no known cure for prion diseases. A better understanding of the molecular mechanism of prion propagation will provide new targets for therapy.
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Animal Prion Diseases
main article: Animal Prion Diseases
author: Athithyan Umakanthan
| Amyloid Plaque Aggregation |
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| Figure 1: Induced BSE and vCJD amyloid plaques in mice. Amyloid plaque is a result of the pathogenesis of BSE [3] |
Animal prion disease is a form of neurodegenerative disease that involves the accumulation of the prion protein (PrP). PrP may exist in two forms: a normal cellular prion protein designated as PrPC or a pathogenic misfolded conformation designated as PrPSc [1]. The infectious prion particle is able to cross the species barrier, allowing animal prion diseases to be transmitted to humans and cause neurodegenerative diseases. These neurodegenerative diseases are incurable, with pathogenesis in the central nervous system that slowly leads to fatality[2]. Animal prion diseases that are most relevant to human health security are bovine spongiform encephalopathy (BSE), chronic wasting disease (CWD) and scrapie. Although all of these diseases are dependent on PrPSc, their symptoms are varied and unique. These specific diseases are of the most concern because the animals that act as a vector for PrPSc are in regular human proximity. As a result, understanding the pathogenesis and the ability of the disease to use animals as reservoirs for PrPSc contributes to identifying effective methods to combat animal prion disease.
Human Prion Diseases
main article: Human Prion Diseases
author: Shuzhengrong Xu
Human prion diseases are a group of fatal neurodegenerative diseases characterized by a misfolded form of the human prion protein. Symptoms of human prion diseases include ataxia, dementia, involuntary muscle contractions and difficulty swallowing [1]. These diseases can be largely categorized as either Iatrogenic, familial or sporadic. In Iatrogenic cases, the misfolded protein is transferred from one host to another during medical treatment and is extremely rare[2]. Familial cases account for less that 15% of all human prion diseases and are cause by genetic mutations in the prion gene[3]. Sporadic cases are the most common and with the cause of disease yet to be identified. Regardless of the cause of disease, all human prion diseases are fatal and without a cure. Current research focuses on uncovering the molecular players in the pathogenesis of the human prion disease as well as the evolutionary significance of the prion gene using a plethora of different molecular approaches and animal models.
Prion-like Neurodegenerative Diseases
main article: Prion-like Neurodegenerative Diseases
author: David Long
Alzheimer’s disease, frontotemporal dementia, and Parkinson’s disease are debilitating neurodegenerative diseases which involve the pathological aggregation of proteins. Alzheimer’s disease involves the aggregation of the amyloid beta into extracellular plaques as well as aggregations of the tau protein into intracellular neurofibrillary tangles. Frontotemporal dementia similarly involves neurofibrillary tangles. Parkinson’s disease, on the other hand, involves Lewy bodies which contain a significant amount of the protein α-synuclein. Like prion diseases, the proteins likely involved in the pathogenesis of these diseases have more than one conformation, and aggregates may be able to “seed” monomers to adopt their conformation [1]. Unlike prion diseases, these diseases are not known to be contagious. There is some in vitro evidence that the aggregates involved in these neurodegenerative diseases may be able to propagate between cells. There is also some in vivo evidence, from studies involving animal models or human studies. There is speculation that aggregates involved in these diseases may propagate between cells via release following cell death, exocytosis, synaptic release, or tunnelling nanotubules [2]. Although some mechanisms involved in the propagation of pathological aggregates in neurodegenerative diseases likely different from the mechanism involved in true prion diseases, if some neurodegenerative disease processes are analogous to those observed in prion diseases this may help researchers develop new treatments for these diseases.