Transmissible Spongiform Encephalopathy – Prion Protein – Kuru Disease

Transmissible Spongiform Encephalopathy – Prion Protein – Kuru Disease

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Introduction: Prions or infectious protein were big news in 1980, when it becomes clear that these proteins cause diseases.

In year 1997, B. Pruisner received the noble prize in medicine for his discovery of prions “An     entirely new genre of disease causing agents.” Even though Prusiner’s work started in 1972, by 2017 we have got only a sort of understanding about prions.

Researchers from case Western Reserve University have synthesized an clear that artificial human prion in June 2018, which is deadly contagious and responsible for causing transmissible spongiform encephalopathy. Their works were published in the journal “Nature Communication” in the first week of June.

Now there may be arousal of a transmissible spongiform encephalopathy?

It is the rare form of brain wasting diseases and the name signifies ‘transmissible’ means infectious in nature, ‘spongiform’ means sponge like and ‘encephalopathy’ signifies disease process in brain or ‘infectious brain disease process where brain become sponge like.’

It is a fatal neurodegenerative conditions in human and animals where the healthy brain tissues are replaced by cluster of tiny liquid filled thin wall cavities and making the brain ‘sponge like’ due to accumulation of misfolded proteins i.e. Prion proteins.

After many years of discovery until now our understanding of prions in the brain has been limited and till now it is a curable, invariably fatal diseases.

History: It is a known for approximately 200 years and is proto-typical prion disease affecting sheep, goats had been known since 18th The crucial break through was achieved in the 1930s by the experimental transmission of Scrapie to goats.

Carleton Gajdusek demonstrated the kuru, a disease affecting the aboriginal people of Papua New Guinea was a TSE. The incubation period of the disease was longer than investigator’s persistence.

William Hadlow suggest that kuru resembled scrapie hence might exhibit a very long incubation period. After influencing by this Gajdusek achieved transmission of Creutz-feldt Jakob Disease(CJD).

History and discovery of prion disease
Pic.1- History and discovery of prion disease

 

Whereas, CJD in human was exceedingly rare. Its incidence is typically  inhabitants / years in Switzerland. However, several aspect of CJD epidemiology continue to be enigmatic and a screen for recognized / hypothetical risk factor for CJD has not exposed any causal factor to death.

 

  • Prion Protein: Prions are the natural human protein, coded by PRNP gene located on the short arm of chromosome no. 20 (between the end of the arm and position 12) known as CD230 (cluster of differentiation).

Expression of the protein is most pre-dominant in the nervous system (cell membranes of neurones), though it found in many other tissue of the body.

  • Structure of the Prion Protein: PrP is highly conserved through mammals consists of a globular domain with 3α-helix and a two strand anti-parallal β-sheet and -NH2 terminal tail and a sort -COOH

The primary sequence of Pr, 253 amino acids converts into mature protein having 208 amino acids long after post-translational modification.

PrP messenger RNA contains a pseudoknot structure (Prion pseudo-knot) which is thought to be involved in regulation of PrP protein translation.

Structure of PrP^c and PrP^sc
Pic.2- Structure of  Pr  and Pr

 

  • Functions of Cellular Form of Prion Protein: All though the exact functions of Pr is unknown and based on structural similarity, it has been proposed that Pr might function as a member of the Bcl-2 family of protein. It might have role in-

 

  • Synapse between neurons that can cause long term memory
  • Uptake of copper into the cell
  • Differentiation neuronal stem cell
  • Neurogenesis
  • Neuritogenesis
  • Neuronal survival via anti-/pro-apoptotic function
  • Red-ox haemostasis
  • Long term renewal of haemopoetic stem cell
  • Activation of T-cell
  • Differentiation and modulation of phagocytosis of leukocytes
  • Altering leukocytes recruitment to site of inflammation

 

  • Difference between Prand Pr:

 

Features   Pr (Normal cellular isoform) Pror Pr  (Scrapie isoform)
1.  Cellular dimorphism 43% α-helical and 3% β-sheet 30% α-helix and 43% β-sheet
2.  Sensitivity to enzyme protease Sensitive  Resistant
3.  Solubility in water Soluble Insoluble
4.  Location Located anchoring to the cell membrane Mainly present in cytoplasmic vacuoles

 

  • Transformation of Prfrom Pr: Prdifferent domains that play different roles in the conversion of PrPr. The first one is stable and ordered ‘core’ domain which contain GPI lipid anchor (Glycosyl Phosphatidyl Inositol) that tethers Pr to the plasma membrane, 3α- helix (helix A, band C) , 2 asparagines amino acid linked oligosaccharides and a protein binding sites capable of lowering the energy barrier for the conversion of Pr to Prwhen Prbinds to protein X (a species specific co-factor necessary for conversion of Prto Pr
Changes after transformation from Pr  to Pr
Pic. 3- Changes after transformation from Pr  to Pr

  

The second domain is a ‘variable’ or disordered domain which interact with Prand changes the Prconformation from unstructured form to the β-sheet of PrDuring conversion, helix A of the core domain of Pr also gets converted into β-sheet.

According to Sanley B. Prusiner’s theory,1997 once infected prion protein (Pr/ Pr) are carried to the neurones, they bind to the normal Pr on the cell surface, as a result, there is release of Pr from the cell surface followed by conversion into Pr/ Pr (as described before), by pot-translational modification by Pr.

When the cells synthesize Pr (new) by repeated cell cycle, a large no. of Pr is formed.

Pr being aggregated forms amyloid like plaques in the brain. As these plaques consist of host proteins, so there is no immune response or inflammation.

Abnormal misfolded proteins are internalized by neurones and get accumulated inside the cytoplasmic vacuoles mostly in the cells of the neurone. Thereby it enhances apoptosis with the help of 14-3-3 protein and large no. of cells are died off and cyst is formed in the brain that causes appearance of sponge form and it degenerates mainly cerebral cortex and cerebellum.

Due to above reasons there is following changes ultimately-

  • Vacuolation of the neurones
  • Formation of amyloid containing plaques and fibrils
  • Proliferation and hypertrophy of astrocytes
  • Fusion of neurones and adjacent glial cell
Coronal section of brain showing the vacuolation in brain due to prion disease
Pic. 4- Coronal section of brain showing the vacuolation in brain due to prion disease

 

  • Disorganisation of Prion Protein: Though it is hypothesized that Pr, the protease resistance forms are responsible for the prion disease, there is a protein sensitive (Pr) but disease associated translational form has also been described.

According to “Protein Only Hypothesis”, we are accepting Pr as the infectious agent, whereas there is “Not Only Protein Hypothesis”, because it is found that 25nm long virus like particle demonstrated in the cell culture with Creutz-feldt Jakob disease and Scrapie. Interestingly, these particles are similar to tubulo-vesicular structure found in all TSE form.

It is generally accepted that prion diseases are prion disease are transmissible, hence the name is transmissible encephalopathy and it is invariably fatal. Though transmissibility may fail in certain disease form associated with amyloidogenesis and there may be a sub-clinical carrier state in different species including human beings.

 

  • Classification of Prion Disease/Transmissible Spongiform Encephalopathy:

No distinct rules/theories can be applied for this classification. TSEs are classified on the basis of their pathogenesis mainly-

  • TSE in Animals:
  • Scrapie Disease: This phenotype of prion disease has been extensively studied. It is commonly found in sheep, goats, mouflons. They are of two types-
  1. Natural Scrapie: It is spreaded by vertical transmission i.e. parent to offspring or rarely by direct contact. After incubation period of 2 years, the affected sheep become irritable and develop intense pruritus, scraping themselves against trees and rocks and hence the name Scrapie . Gradually, emaciation and paralysis occur leading to death.
  2. Experimental Scrapie: The disease can be experimentally transmitted to various animals (research purpose) to several breeds of sheep and other animals by infection of natural tissues of infected sheep. In hamsters and mice, the incubation period is less and facilitated the study of the disease. Different breeds of sheep exihibit marked genetic defects in susceptibility to the infection 0-80% , whereas goats have 100% susceptibility.
  • Transmissible Mink Encephalopathy: Scrapie like disease in mink transmitted by feeding the mink on scrapie infected sheep meat.
  • Bovine Spongiform Encephalopathy / Mad Cow Disease: It commonly occurs in cows, lions, tiger, cheetah, puma, bison and exotic antelopes. It was enzootic in cattle in Great Britain since 1986. The epidemic in 1993 infecting over 1 million cattle with infection spreading to European countries. BSE in transmitted due to practice of feeding the cattle with meat and bone meal contaminated with Scrapie / BSE proteins.
  • Chronic Wasting disease: It occurs in captive and free range cervids of mule deer, elk.

 

  • Human TSE:
  • Familial CJD: It is the second most group of human prion disease. Disease prevalence rate is approx 10-15%. It occurs due to mutation in PRNP gene. Most common mutation occurs at 200th codon where glutamic acid is converted into lysine and as a result the entire potein is misfolded.

 

  • Variant of familial CJD: It runs in families. There are following variants-
  • Fatal familial insomnia: It is due to the germ line mutation in PRNP gene at 178th codon where aspartic acid is converted into asparagines. Therefore, misfolded prion proteins build up mainly in the thalamus, that regulates sleep rather than causing the typical spongiform degeneration in the cortex and cerebellum, occurs in most other types.
  • Gerstman- Straussler- Scheinker Syndrome: It is extremely rare form of neurodegenerative disorder of brain. It is almost always inheritent and is found only in few families around the world. Onset of the disease usually occur between the ages of 35 and 55 years. It slowly progresses and is usually lasting for 2-10 years. There may be polymorphism at codon 129/ codon 219 of PRNP gene and may associate with pro to lew point mutation at codon 102 of the PRNP gene, as found in large new Italian family in 1997.

 

  • Variant CJD: It is caused by eating the meat of animals having prion in the muscle tissues. Prions enter into blood stream after absorbing through intestine. Somehow these proteins crosses blood brain barrier and enters into the neurone by a process called adsorptive endocytosis, where the plasma membrane of the nerve cell folds inward to bring in substance otherwise not able to cross plasma membrane by themselves. As the prion is in the blood stream, this disease can be spread by blood transfusion. As it was occurred in UK, 1980. In Britain,1996, there was raised fears of infection through eating BSE infected beef among younger (below 45 years).

 

 

  • Iatrogenic CJD: It is caused by medical procedures or by equipment used for that procedures like-
  1. Corneal transplant gets contaminated and infects healthy individuals
  2. Electro-encephalogram (EEG) electrode implantation
  3. Duramatter graft implantation (>160 cases have been recorded
  4. Human growth hormone and pituitary gonadotropin therapy (>180 cases have been recorded)
  5. Mostly iCJD occurs in patient between 50-75 years.

 

  • Total cases of iatrogenic CJD world-wide:*
Mode Cases(n) Mean incubation period (years) Clinical
Neurosurgery 4 1.6 Visual/cerebella
Depth electrodes 2 1.5 Dementia
Corneal transplant 3 15.5 Dementia
Dura mater 136 6 Visual/cerebella
Human Growth Hormone 162 12 Cerebellar
Human Gonadotropin 5 13 Cerebellar

*Data courtesy of Dr P. Brown.

 

  • Sporadic CJD: It is the major type of human prion disease (85-90%). There is no clear cause behind it. It mainly occurs due to spontaneous mutation in the 129th codon of the PRNP gene where valine is converted into methionine.

 

Different types of Prions affecting different areas of brain
Pic. 5- Different types of Prions affecting different areas of brain

 

  • Kuru Disease: (‘kuru’ = tumor)

It was identified in 1957. Kuru was a mysterious disease seen only in the fore-tribe inhabitating the eastern highlands of New Guinea. The disease has incubation period of 5-10 years and led to progressive cerebral ataxia and tremors, ending fatally in 3-6 months.

The infection is believed to have been introduced through cannibalism and maintained by the trial custom and eating the dead bodies of relatives after death as a part of ritual. The disease disappears following the abolition of cannibalism in New Guinea. Carlton Gajdusek was awarded Noble prize for medicine in 1976 for his important contribution on Kuru.

 

  • Clinical manifestation of Prion Disease:

Prion disease is a slow virus infection. Incubation period of prion diseases from months to years (longest 30 years) but once the disease sets in, progression is very fast. There are 3 phases –

  • Pro-dermal phase (3-5 months)
  • Disease symptoms
  • Death

The disease symptoms vary depending on the type of prion disease-

  • Sporadic CJD: The symptoms mainly affect the workings of the nervous system (neurological symptoms) and these symptoms rapidly worsen in few months.
  • Variant CJD: Symptoms that affect a person’s behaviour and emotions (psychological symptoms) will usually develop first.
  • Initial neurological symptoms:
  1. difficulty in walking caused by balance and co-ordination problems
  2. ataxia
  3. numbness or pin and needles in different parts of the body
  4. slurred speech
  • Initial psychological symptoms:
  1. Severe depression
  2. Intense feeling of despair
  3. Difficulty in sleeping (insomnia)
  • Advanced neurological symptoms:
  1. Muscle twitches and spasms
  2. Loss of bladder and bowel control
  3. Swallowing difficulty (dysphagia)
  4. Loss of voluntary movements
  5. Extreme muscle weakness that causes inability to walk and stand
  6. Fatal familial insomnia
  7. Myo-clones (quick, jerky movement of the muscle)
  8. Exaggerated startle response
  • Advanced psychological symptoms:
  1. Dementia (no memory, power of decision making an reasoning)
  2. Loss of memory which is often severe
  3. Problems concentrating
  4. Feeling agitated
  5. Aggressive behaviour
  • Final stages: As condition progresses to its final stages, people with all forms of CJD will become totally bedridden. They often become totally unaware of their surroundings and require around the clock care.

Death inevitably follow, usually either as a result of an infection, such as pneumonia (a lung infection) or respiratory failure where the lung stops working and the person becomes unable to breathe.

 

  • Diagnosis: The diagnosis should be considered in any individual presenting with a rapidly progressive dementia. When other common causes have been excluded and there is other early neurological feature (especially cerebellum/visual). There are mainly 3 investigations of particular diagnostic utility – 1) Electroencephalogram (EEG)

2) CSF 14-3-3 protein

3) MRI

Testing the different types of human prion disease are distinguished by the clinical characters and classified according to internationally recognised published criteria, updated in 2010 and retrospectively applied to all referral since January 2010. The surveillance was last updated in January 2017.

 

Diagnostic criteria NCJDRSU for CJD surveillance across the UK: (The National CJD Research and Surveillance Unit is part of the centre for Clinical Brain Science, University of Edinburgh and is a part of the Deanery of Clinical Science in the College of Medicine and Veterinary Medicine)

  • Electroencephalogram: The EEG shows a progressive deteriotion in the normal background rhythms and in around 2/3rd of cases, appearance of Periodic Sharp Wave Complexes (PSWCs). The important points to be noted-
  • The absence of PSWCs does not exclude the diagnosis
  • PSWCs may be in other conditions (for example hepatic encephalopathy drug toxicity and rarely Alzheimer’s disease)
  • If PSWCs are absent on an initial EEG, repeat EEG may show development. (repeat testing should be considered at around weekly intervals)

 

  • CSF 14-3-3 proteins: CSF 14-3-3 proteins is a normal neuronal protein that has no specific connection to CJD, being released into the CSF following neuronal damage. It has specific diagnostic utility in CJD. However, CSF 14-3-3 concentration can be reasonably readily differentiated from sporadic CJD on clinical grounds. A positive CSF 14-3-3 test may therefore strongly supported specificity and sensitivity (both 94%) are valid only in an appropriate clinical context.

 

  • MRI (Magnet Resonance Imaging): Cerebral imaging is a vital part of the exclusion of other diagnosis and normal brain imaging in the face of a rapidly progressive, devastating encephalopathy, may lead to a consideration of sCJD. However, in some cases MRI shows a characteristic signal change in putamen and caudate. Occasionally high signal may be seen in the cerebral cortex, generally focal and reflecting the particular clinical feature at the time imaging. Significant atrophy is usually if imaging is undertaken within 3 months of onset of disease.

 

  • Measurement of Pr: It is measured by conformation dependent immunoassay is the most definitive diagnostic tool for prion disease.

 

  • Neuropathological diagnosis in Brain biopsies: The pathologic hall-marks of prion disease seen under light microscopy, are spongiform degeneration and astrocytic gliosis with lack of inflammatory response.

 

  • Sequencing the PRNP gene: It is to identify the mutation – this is important in familial forms of prion disease.

 

 

  • Treatment:

There was no disease like prion before. So till now it is not clear which strategy will lead to a treatment or cure. Scientists are investigating a lot of different possible ways of treating these disease.

  1. Small molecules: Within the fields of molecular biology and pharmacology, a small molecule is a low molecular weight organic compounds (<9000 Daltons) that may regulate a biological process, with a size of 1nm. Most drugs are small molecules.
  2. Antibodies: Anti-PrP antibodies have shown to eliminate Pr from the cultured cell but they failed to do so in vivo.
  3. Gene Silencing
  4. Several drugs like quinacrine

 

  • Decontamination: Prions are resistant to most of common sterilization procedures.
  • Autoclaving at 134ᵒc for 1-1.5 hours
  • Treatment with 1(N) NaOH for 1 hour
  • Treatment with 0.5% sodium hypochlorite for 2 hours

If the prions bound to the stainless steel should be treated with an acidic detergent solution prior to autoclaving; rendering them susceptible to inactivation.

  • Conclusion: Though it is a rare form of neurodegenerative disorder, for example 300-350 cases are reported in the USA per year, but it often progresses rapidly and currently it is incurable. So, till now prions are scary ailment.

In this year June 2018, researcher from case Western Reserve University have synthesized an artificial prions, though a new strain of prion sounds terrifying, but this research could be a bold new step in helping to treat prion disease by discovering auxiliary factors and developing therapeutic approaches to block them.

Artificial prion protein
Pic. 6- Artificial prion protein

 

 

  • Reference:
  1. Essential of Medical Microbiology by Apurba Shankar Sastry and Sandhya Bhat k. Page no.- 521-524
  2. Ananthanarayan and Paniker’s text book of microbiology, 10th edition, Page no.- 560-561
  3. Transmissible spongiform encephalopathy from ‘Zoonotic Disease is in Northern Euresia ,2015’. Prion disease- Pawel P. Liberski, James W. Ircnsicle in ‘Neurobiology of Brain Disorder’; Prion disease- Adrano Aquzzi (M.D., PhD, DVM, hc, FRCP, FRC Path), Markus Glatzel (M.D.) in Neurobiology of Disease.
  4. ISRN Infectious Disease, Volume 2013, Article ID 387925, 11Pages
  5. Prion disease: Am J Pathol. 2008 March; 172(3) Page no.- 555-565
  6. Athena Yenko, June7, 2018
  7. GEN News Highlights, June 6, 2011
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