Prion diseases in other words known as transmissible spongiform encephalopathies (TSEs) belong to a type of progressive neurodegenerative conditions.

Condition is caused due to mutations and changes to its normal shape which lead to forming the rogue form of the naturally occurring normal prion protein encoded by the gene PRNT in humans. Normal form of the prion protein mainly active in the brain and few other tissues has a function involved in moving charged copper ions into the cell. However, different polymorphisms and specific point mutations taking place in different regions of the gene leads to the formation of harmful prion proteins. These rogue proteins are capable of converting other surrounding normal protein into their affected form. Accumulation of disease causing prion proteins leads to fatal conditions such as Creutzfeldt-Jakob disease (CJD) which directly affects the nervous system and areas of the brain that control coordination. The inherited form of the disease shows an Autosomal dominant inheritance pattern.

CJD is a disorder which affects the nervous system in humans hence classified as a neurodegenerative disorder. This disease is identified as one of the most common human prion diseases. Although CJD is a common Prion disease, the incidence is very rare occurring in about 1 in1 million people.(1) Disease can be separated into two major classes. One is the classic CJD which is formed of two types Sporadic and fCJD. Sporadic CJD represents most of the cases shown to have an onset of around 65yrs old and Familial CJD is inherited via an autosomal dominant pattern which means that only one mutant allele is required to show the disease phenotype.

Patients with CJD show few key symptoms and they are quite significant. In most cases the disease is fatal within 8 months since the onset hence its not usually confused with other forms of dementia which includes diseases such as Alzheimers where symptoms worsen at a much slower rate. Some of the major symptoms observed in CJD patients include rapidly

accumulating memory loss and changes to ones personality and disorientation. Patients are also known to show signs of hallucination and are unfortunately accompanied by physical problems such as lack of coordination leading to walking difficulties and seizures and changes to posture. (2) Current diagnostic procedure is initially based on symptoms that can be physically noticed. In the early stages a mental examination is conducted to confirm progressive signs of dementia. Towards the later stages of the disease its diagnosed via administration of the motor system for increased abnormal reflexes, muscle spasms signs of muscle loss. Signs of blindness can also be confirmed via an eye examination. Currently there are few tests that can be carried out to diagnose the disease. Some of these include typical blood tests to rule out other forms of dementia which is done upon first seeing signs of memory impairment. Scans such as CT and MRI of the brain are done (2) to reveal affected areas of the brain mainly focusing on changes to the cerebellum which controls normal coordination.

In terms of treatments to cure or control this fatal disease there is currently none available. Drugs and treatment programs such as amantadine, steroids, interferon, acyclovir, antiviral agents, and antibiotics (3) on humans havent been successful in a significant way. Hence the only type of treatment thats available for CJD patients involve methods targeted to ease the symptoms to make the patients feel comfortable. Opiate drugs are used to help manage the pain and there are other drugs prescribed to relieve myoclonus effects (3). As mentioned earlier CJD is a prion disease however these proteins occur in normal form and is only infectious when they misfolds into its infectious state. Infectious prion proteins clump together and results in the neuronal loss (4) and brain related damage observed in the cerebellum that leads to the adverse symptoms.

Gene that produces the mRNA for the synthesis of prion protein in humans is called the PRNP gene protein encoded by it belongs to the class of genes called the PRP (Protease Resistant Proteins). It is also known that 20kbo upstream of this gene is another gene that encodes for a protein that is structurally and functionally similar.(5) Gene mapping techniques used by geneticists have been fruitful in identifying the cytogenic location of the PRNP gene to be 20p13. This number explains that it is found on chromosome 20 in the (p) arm which is the shorter one at the position 1 towards the telomere region. In terms of molecular location is from base pairs 4,666797 to base pair 4.682,233 of the given chromosome. Studies have discovered information that explains the structure of the PRNP gene. The PRNP gene is 22438bp long and in its 5 prime end of the transcription initiation site is a GC rich region which is a feature usually observed in housekeeping genes that produce proteins that regulates the cellular functions. Typical promoter region contains a TATA box but, in the case of PRNP its a CCAAT box and has several binding sites for few transcriptional factors. It was also discovered that the gene has two exons which are translated during protein synthesis and inbetween is a very large intron (6) region which is spliced out from the pre mRNA. There is also an exon region but it cant be considered an exon since its not 150bp long. Protein resulting from the PRNP gene has a very unstable octapeptide repeat and that polymorphisms observed in the regulatory regions of the gene have shown to put CJD susceptible individuals at risk. It is important to note that both normal and infectious forms have the same primary polypeptide sequence. Congenital presence of mutant form of the gene is purely due to genetic inheritance of familial CJD (fCJD). One of the major mutations responsible for this form of the disease is a point mutation taking place at the codon129 which shows heterozygosity of methionione or valine. Amongst the Caucasian population genotype frequency at this codon: met homozygous 37%; met/val heterozygous 51%; val homozygous 12% (7). There have been cases where insertion mutations of octapeptides ranging from just

1 (24bp) upto 7 octapeptides occuring in the repeat regions and all these mutations are within the codon region from 51-91. (8) Diagram below depicts the points at which these common mutations take place.

Human PRNP gene mutations and polymorphism locations

PRNP gene in humans show signs of homology which is when proteins or DNA sequence in context having shared ancestry. Some of the most common homologies of prion protein gene in homo sapiens are the chimpanzee, rhesus monkey, dog, house mouse & Norway rat (9) and no orthologous genes have yet been confirmed.

References

(1) Bosque PJ. Prion diseases. In: Goldman L, Schafer AI, eds. Cecil Medicine. 24th ed. Philadelphia, Pa: Saunders Elsevier; 2011:chap 424).

(2) Creutzfeldt-Jakob disease - National Library of Medicine - PubMed Health. 2013. Creutzfeldt-Jakob disease - National Library of Medicine - PubMed Health. [ONLINE] Available at: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001792/. [Accessed 23 August 2013].

(3) Creutzfeldt-Jakob Disease Symptoms, Causes, Treatment - How is the Creutzfeldt-Jakob disease treated? - MedicineNet. 2013. Creutzfeldt-Jakob Disease Symptoms, Causes, Treatment - How is the Creutzfeldt-Jakob disease treated? - MedicineNet. [ONLINE] Available at: http://www.medicinenet.com/creutzfeldtjakob_disease/page8.htm#how_is_the_disease_treated. [Accessed 23 August 2013]

(4) Creutzfeldt-Jakob Disease Fact Sheet: National Institute of Neurological Disorders and Stroke (NINDS). 2013. Creutzfeldt-Jakob Disease Fact Sheet: National Institute of Neurological Disorders and Stroke (NINDS). [ONLINE] Available at: http://www.ninds.nih.gov/disorders/cjd/detail_cjd.htm#235903058. [Accessed 23 August 2013].

(5) PRNP Gene - GeneCards | PRIO Protein | PRIO Antibody. 2013. PRNP Gene GeneCards | PRIO Protein | PRIO Antibody. [ONLINE] Available at: http://www.genecards.org/cgi-bin/carddisp.pl?gene=PRNP. [Accessed 23 August 2013].

(6) PRNP prion protein [Homo sapiens (human)] - Gene - NCBI. 2013. PRNP prion protein [Homo sapiens (human)] - Gene - NCBI. [ONLINE] Available at: http://www.ncbi.nlm.nih.gov/gene?cmd=retrieve&dopt=full_report&list_uids=5621. [Accessed 23 August 2013].

(7) Mutations in Prion Protein Gene. 2013. Mutations in Prion Protein Gene. [ONLINE] Available at: http://www.federationofscientists.org/pmpanels/tse/priprogene.asp. [Accessed 23 August 2013].

(8) Prnp prion protein [Mus musculus (house mouse)] - Gene - NCBI. 2013. Prnp prion protein [Mus musculus (house mouse)] - Gene - NCBI. [ONLINE] Available at: http://www.ncbi.nlm.nih.gov/gene/19122. [Accessed 23 August 2013].

(9) HomoloGene - NCBI. 2013. HomoloGene - NCBI. [ONLINE] Available at: http://www.ncbi.nlm.nih.gov/homologene/7904. [Accessed 23 August 2013].