Discovery of unusual pathogens and how they cause diseases



Prion is a misfolded protein that causes several neurodegenerative diseases , collectively called transmissible spongiform encephalopathies(TSEs) in animals including humans.This small infectious agent is an aberrant form of a protein called cellular prion protein(PrPC).As stated in Ingram’s book “Fatal Flaws”, before 1982 the tube-nose birds of southern seas were the only prions on earth. But, in 1982, a paper published by American scientist, Stanley Prusiner not only relegated these ornithological prions to back pages but also completely changed the world of CJD,Kuru,Scrapie and a soon-to-be expanded list of diseases.

Fig 1 :Prion protein PrP. Flexible portions of the protein

that are not included in the structures are shown with dots.

Cellular prion protein(PrPc) is a membrane associated protein found in many eukaryotic cells. It is found abundantly on the surface of cells in the central nervous system.It anchors to the neurons via a sugar moiety and functions by transmitting signals between adjacent neurons. A slight change in its three dimensional structure results in a variant insoluble isoform(PrPSc) which hampers the normal process of sensory signal transduction .


In the 18th century, a strange disease affected Merino sheep.It was termed Scrapie owing to the fact that the affected sheep scraping against the fences, was a clinical diagnostic factor.To understand the nature of the scrapie agent, various experiments were performed including filtration and inactivation by nucleases on scrapie infected tissue.In 1954,Sigurdsson suggested that a slow virus caused this disease due to its long incubation period.

While this was suggested, another neurological disorder was discovered among the Fore tribe in Papua New Guinea called kuru(meaning ‘trembling’ or ‘fear’ in Fore language).Kuru presented similar symptoms to CJD(Creutzfeldt Jakob Disease) and Scrapie.It was not until 1959 that Kuru,CJD and Scrapie were found to be distinct forms of same neuropathy. Meanwhile,some scientists hypothesized that nature of scrapie agent could be a protein.They used ionizing radiation and chemicals(formalin) which usually inactivate pathogens that contained nucleic acid (like viruses and bacteria).In 1982,Stanley Prusiner published a paper in journal Science titled

“Novel Proteinaceous Infectious Particles Cause Scrapie” supporting this idea. Although it was an already established idea , it set off a firestorm among the scientific community , because Prusiner forcefully argued that the infectious agent causing Scrapie could not be anything but a protein and even coined a new name called ‘Prion’ for it.

The Prion hypothesis postulates that these neurodegenerative diseases were not caused by conventional pathogens but by a protein that has misfolded and became abnormal.Prusiner along with other scientists (Bolton and McKinley) successfully inactivated the infectious agent, isolated from diseased animals, by methods that destroyed proteins which further strengthened the prion hypothesis.


Since the blueprint for making this protein is already present in the body, therefore prions do not cause any host immune response.In addition to this, what baffled researchers the most was the way these infectious agents were causing disease Fig:2 Amyloid complex of prion protein HET-s.

by defying the central dogma. As Crick quotes ‘Once (sequential)information has passed into protein , it cannot get out again’.However, prions seemed to break this rule.These abnormally folded proteins do not undergo replication in host cell but merely act as a template and instigate normal proteins to convert into misshapen variants.

These misfolded proteins further act as templates and cause more proteins to become abnormal in a somewhat domino effect leading to a chain reaction and accumulation of prions in the CNS(Central Nervous System) tissue. Abnormal prion protein(PrPSc) cannot be degraded by proteases and thus aggregates and forms long chains called amyloid fibers which are toxic to neurons.This accumulation apparently leads to the neurofibrils getting entangled and affects synapse function. Eventually, deterioration and loss of nerve cells takes place .Death of these nerve cells creates tiny holes in the brain rendering it a swiss-cheese or sponge-like appearance when observed under a microscope.

Misfolded proteins causing disease is not a new concept as it is seen in the case of sickle cell anaemia too.But, what sets prion apart,is the fact that the three dimensional structure of the prion protein is responsible for its disease causing properties.Central dogma, on the other hand, states that this information is usually encoded by DNA or RNA.

Fig :3 Schematic representation of the potential mechanism of neuroinvasion in transmissible spongiform


Recent studies have shed light on the molecular structure of cellular PrPC. The structure has been determined at atomic resolution using NMR Spectroscopy and X-ray crystallography.However, structure of PrPSc has not yet been fully deciphered as the abnormal protein could not be purified in a soluble, non-aggregate form in sufficient quality and quantity. Cryoelectron microscopy and structural modelling has revealed that PrPSc is mainly composed of β-sheets which form a left-handed beta-helix unlike PrPC which mainly consists of alpha-helices.Three PrPSc molecules apparently form a primary unit.The disease causing agents are thus PrPSc aggregates whose catalytic activity depends on the size of the particle.

Many studies have explored the structural parts of proteins involved in transition of cellular PrPC into fibril-forming isoform PrPSc.A recent study has provided some insight into the underlying mechanism of human prion protein misfolding.It provides evidence on how a misfolding intermediate of human PrPC is responsible for aggregation of abnormal protein into amyloids.

Several newly discovered prions and prion-like proteins do not cause any diseases and on the contrary some are turning out to be important for biological processes.

Despite overwhelming experimental evidence and research, the existence of prions remained debatable for decades.Recent breakthroughs have provided evidence that misshapen protein is an active component of the infectious agent and transmission of disease depends on self replication of the infectious folding of the prion protein.But it is still unclear whether another molecule, besides the misfolded prion protein, might be an essential component of the infectious agent.

Harshita Kukreja

Department of Biochemistry and Biotechnology

St.Xavier's college



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