Jiacm 2003; 4(4): 334-6 Phd I year, Department of Physiology, Louisiana State University Medical Center, New Orleans, la-70112, usa

L E C T U R E   N O T E S

JIACM 2003; 4(4): 334-6

* PhD - I Year, Department of Physiology,

Louisiana State University Medical Center, New Orleans, LA-70112, USA.

** Madras Medical College, Chennai.

Prions – Proteinaceous Infectious Particles

Pramood C Kalikiri*, Reena G Sachan**

Key words

Proteinaceous infectious particles, Structure of prions, Properties of prions, Human prion disease, Pathogenesis of human prion

disease.

What are prions?

The word itself derives from ‘proteinaceous infectious

particle’; meaning that the infectious agent consists

only of protein with no nucleic acid genome. Prions

are the only known example of infectious pathogens

that are devoid of nucleic acid. All other infectious

agents, like bacteria, viruses, fungi possess genomes

composed of either DNA or RNA that direct the

synthesis of their progeny

1,2

.

Properties of prions

The infectious agent (Prion) consists primarily of a protein

found in the membranes of normal cells, but in this case

the protein has an altered shape or conformation – PrP(

Sc

)

– called scrapie isoform. Prions reproduce by recruiting

normal cellular prion protein PrP(

C

) and stimulating its

conversion to the disease-causing (scrapie) isoform

PrP(

Sc

)

1,2

, producing a chain reaction that propagates the

disease and generates new infectious material. The

process by which prions stimulate the conversion of PrP(

C

)

to PrP(

Sc

) is not clear.

This mysterious infectious agent is resistant to ultraviolet

radiation and X-rays, which breaks down nucleic acids,

suggesting the absence of nucleic acid

3

, but is susceptible

to substances that disrupt proteins. Hence, prions remain

infectious even after being exposed to treatments that

destroy nucleic acid.

A major feature that distinguishes prions from viruses is

that PrP(

Sc

) is encoded by a chromosomal gene

4

. The gene

for this protein has been successfully cloned, and studies

using transgenic mice have bolstered the prion

hypothesis.

According to Dr. Anders Hedberg, phenomenon much like

prion infection exists in yeast. In the yeast, there is passage

of a particular genetic trait from mother cells to daughter

cells along through the cell cytoplasm, rather than the

nucleus which is the site of genetic information.

Structure of prions

The structure of PrP(

C

) and PrP(

Sc

) have been studied by

manufacturing these proteins in

 E. coli bacteria that were

altered through recombinant DNA techniques. The

polypeptide chains of PrP(

C

) and PrP(

Sc

) are identical in

amino acid composition but differ in their three-

dimensional, folded structures (conformations). PrP(

C

) is

rich in alpha-helixes (spiral-like formations of amino acids)

and has little beta-sheet (flattened strands of amino acids),

whereas PrP(

Sc

) is less rich in alpha-helixes and has much

more beta-sheet

5

. This structural transition from alpha-

helixes to beta-sheet in PrP is the fundamental event

underlying prion diseases.

What do they cause?

Prions have been implicated as a causative factor in a

number of fatal neurodegenerative diseases in humans –

such as Creutzfeldt - Jakob disease (CJD), Kuru, and

Gerstmann-Sträussler-Scheinker (GSS) disease. Prions also

cause disease in a wide variety of other animals, including

Scrapie in sheep and bovine spongiform encephalopathy

(BSE) in cows. These diseases are collectively known as

transmissible spongiform encephalopathies

6

.

Prion diseases may be manifested as infectious, genetic,

or sporadic disorders. No other group of illnesses with a

single cause has such a wide spectrum of clinical

manifestations. Prion disease in humans (CJD, GSS, and

Kuru) have a broad spectrum of clinical manifestations,

including dementia (loss of memory), ataxia (instability

of gait), insomnia, paraplegia (weakness of the

extremities), paraesthesia’s (abnormal sensory

perception), and deviant behaviour.

Aetiopathogenesis of human prion diseases

The cause of CJD was unknown for many years; it occurred

seemingly randomly, at a very low incidence. The

infectious form of CJD is believed to be due to eating

infected cows meat. Inherited cases of CJD and GSS may

result from mutations in the PrP gene which encodes for

stable form of prion protein PrP(

C

)

7,8

. Mutations cause PrP(

C

)

to flip into an abnormal form i.e., PrP(

Sc

) that causes the

disease by associating with PrP(

C

) and converting it to

PrP(

Sc

) in an exponential process.

The abnormal prion protein PrP(

Sc

) often accumulates in

neurons because the cellular mechanisms for removing

them are ineffective

3

. They completely clog the infected

brain cells. The cells misfire, work poorly, or don’t work at

all. Ultimately, infected prion-bloated brain cells die and

release prions into the tissue. These prions then enter,

infect, and destroy other brain cells

9

. This process

continues and eventually the brain looks more like swiss

cheese. The medical term for the prion diseases is

“spongiform encephalopathies,” meaning brain disease

wherein the sick brains (‘encephalo’ is Greek for brain;

‘pathy’ is Greek for disease) are riddled with holes and have

taken the form of sponges

1,2

.

In the 1950s, an epidemic transmissible disease called

Kuru, similar to CJD, was identified in the Fore tribe of

Papua New Guinea. Transmission of the disease

occurred during a ritual funeral process in which the

brain of a dead tribe member was removed from the

skull, cooked, and eaten

3

.

D. Carleton Gajdusek, working at the US National

Institutes of Health, demonstrated that extracts of

brain prepared from people who had died of CJD or

Kuru could cause a similar disease when inoculated

into the brain of chimpanzees, thus suggesting the

presence of an infectious agent. Similar experiments

in mice also produced identical results.

Scientists now speculate that the prions that started out

in sheep suffering from Scrapie made their way into cows

and then moved more recently into humans

10,11

. Cattle are

fed meal made from sheep “offal,” which includes the

bones and other waste parts of sheep carcasses

1,2

.

Conclusion

Recently, the general public has become interested in

prions because of the epidemic of BSE, more commonly

known as mad cow disease. Hundreds of thousands of

infected animals have been eaten by Europeans and

particularly the British over the past 10 years. Research

work suggests that the infected meat may pose a threat

to human health, but the significance of that threat may

not become apparent for years. The US Department of

Agriculture claims that BSE has not been identified in any

US cattle so far

12

, hence it is generally considered a British

problem.

Future direction for research

1.

The exact mechanism by which prions stimulate the

conversion of PrP(

C

) to PrP(

Sc

).

2.

Drugs that can prevent the access of prions from its

site of entry to the brain.

3.

Drugs that can effectively eliminate prions from the

infected brain cells.

4.

It is likely that prions can be a causative factor in a

variety of currently enigmatic neurodegenerative

diseases in which brain cells are destroyed and the

nervous system deteriorates. Alzheimer’s disease and

Parkinson’s disease are two prime candidates.

References

1.

Aguzzi A, Weissmann C. Spongiform encephalopathies: a

suspicious signature. 

Nature (News and Views) 1996; 383:

666-7.

2.

Ironside JW. Prion diseases in man. 

J Pathol 1998; 186 (3):

227-34.

3.

Roos RP. Prion diseases. 

N Engl J Med 1997; 337 (14): 1016-7.

4.

Prusiner SB. Prions. 

Proc Natl Acad Sci USA 1998; 95: 13363-83.

5.

Pan K-M, Baldwin M, Nguyen J 

et al. Conversion of (alpha)-

helices into (beta)-sheets features in the formation of the

scrapie prion proteins. 

Proc Natl Acad Sci USA 1993; 90:

10962-6.

6.

Haywood AM. Transmissible spongiform encephalopathies.

N Eng J Med 1997; 337: 1821-8.

7.

Hansen M. Creutzfeldt-Jakob disease. 

N Eng J Med 1999;

Journal, Indian Academy of Clinical Medicine     Vol. 4, No. 4     October-December 2003

335

340: 1687-1688; discussion 340: 1689.

8.

Matthews WB. Transmission of Creutzfeld-Jakob disease.

Lancet 1994; 343: 1575-6.

9.

Prusiner SB. The prion diseases. 

Scientific American 1995; 272:

48-57.

10. Wells GAH, Scott AC, Johnson CT 

et al. A novel

progressive spongiform encephalopathy in cattle. 

Vet

Rec 1987; 121: 419-20.

11. Brown P, Will RG, Bradley R 

et al. Bovine spongiform

encephalopathy and variant Creutzfeldt-Jakob disease:

background, evolution, and current concerns. 

Emerg Infect

Dis 2001; 7: 6-16.

12. Roos RP. Controlling new prion diseases. 

N Eng J Med 2001;

344 (20): 1548-51.

336

Journal, Indian Academy of Clinical Medicine     Vol. 4, No. 4     October-December 2003

C A S E   R E P O R T

JIACM 2003; 4(4): 337-9

* Registrar, *** Postgraduate, **  Postgraduate, Department of Ophthalmology **** Assoc. Professor,

***** Professor, Department of Medicine, @ Professor, Department of Pathology,

Indira Gandhi Medical College, Shimla -171 001 (Himachal Pradesh).

Alport Syndrome

Sanjay K Mahajan*, Sumeet Sud**, Bhrigu Raj Sood***, RK Patial****,

Neelam Prashar@, BS Prashar*****

Abstract

A case of Alport syndrome (AS) having progressive dysfunctions in eyes, ears, and kidneys is presented. It had all the four diagnostic

components – family history, lenticonus, deafness, and nephritis. The combination of both anterior and posterior lenticonus was

present.

Key words : Hereditary nephritis , Familial nephritis.

Introduction

In 1927, Cecil A Alport described 3 generations of a family

with combination of progressive hereditary nephritis and

deafness. The eponym Alport syndrome (AS) was coined

in 1961

1

. It is a genetically heterogeneous disease

commonly caused due to a defect in the a5 subunit of

type IV collagen located on X chromosome Xp 29. The a5

subunit is a major component of basement membranes

of glomerulus, cochlea, retina, lens capsule, and cornea.

Rarely, it may be caused due to a defect in the a3 or a4

subunit. The characteristic histo-pathological feature is

progressive degeneration of basement membranes in

eyes, ears, and kidneys. Eye changes comprise of anterior

and/or posterior lenticonus, lenticular opacities, and

recurrent corneal ulcerations. Ear changes result in sensori-

neural deafness. In kidneys, the lack of a3, a4, and a5 chains

of type IV collagen are replaced by a1 and a2 chains.

Basement membrane changes in kidneys pass through

various stages from normal to thinning and progressing

to thickening, splitting, and degeneration manifesting as

asymptomatic urinary abnormalities to chronic renal

failure

1-3

.

Case report

18 years old male presented to eye OPD with a history of

progressive diminution of vision for last ten years. He was

unable to achieve satisfactory vision despite repeated

change of glasses for refractive errors. On questioning, he

also told about non-progressive impairment of hearing since

childhood. There was no history of ear discharge, giddiness,

and tinnitus. There was no history of drug intake, headache,

vomiting, cranial nerve palsy, or focal neurological deficit.

His family history revealed that his younger brother had

died of congestive heart failure with renal failure at the

age of 14, and both of his maternal uncles had died of

renal failure. His three sisters are healthy and had normal

ophthalmological and urine examination.

His general physical examination was non-contributory

and he was normotensive. Eye examination revealed visual

acuity of 6/60 in right eye and 6/24 in left eye without any

improvement with pinhole. Intraocular pressure and

indirect ophthalmoscopy was normal. Slit lamp

examination showed normal anterior chamber, distorted

anterior spherical curvature with anterior coning (Fig. 1)

and posterior coning (Fig.  2) of lens with lenticular opacity.

Distant direct ophthalmoscopy revealed positive oil

droplet reflex. Hearing test showed a positive Rinne’s test,

Family tree