ABSTRACT way to distinguish between the two polypeptide



Prions are proteins
that obtain complementary conformations that have the potential to become
independently-propagating. The process of proteins becoming prions is normally
supplemented by a surge in B-sheet protein structure and a propensity to
aggregate to oligomers. Certain prions have the characteristics to be
beneficial and perform vital and important cellular functions, however there
are some prion that are known to cause neurodegenerative disorders. Prions are
that composed of prion proteins (PrP) are believed to cause many transmissible
spongiform encephalopathies (TSEs). In both mammals and fungi, over a dozen of
proteins have been acknowledged as those that can become prions. In recent
years there has been a vast escalation in evidence claiming that prions cause a
wide variety of neurodegenerative disorders such as Alzheimer’s and Parkinson’s




Many neurodegenerative
disorders occur when someone reaches an elder age, a wide array of research and
evidence would argue that some neurodegenerative disorders are caused by Prion
proteins (Prusiner SB, 2012). Prions occur when regular proteins obtain complementary
conformations that have the potential to become independently-propagating.
Prions within humans are created by the use of normal cellular prion protein
(PrPC). A major feature that characterises prions from viruses is
that (PrPsc) is known to be encrypted by chromosomal gene (Prusiner
SB, 1998). The polypeptide chains of PrPC and PrPsc are
known to be alike, however the way to distinguish between the two polypeptide
chains is to analyse their three-dimensional structures and forms. The PrPC
when witnessed is known to be composed in high quantities of a-helixes
and only a slight amount of B-sheet, however in comparison, PrPsc only
is composed of two a-helixes structures and consist of a lot more b-sheets
(Baldwin et al., 1990). Since the study of Prions has been carried out, four
prime notions have been discovered, the first is that prions are the one and
only contagious pathogens that are lacking nucleic acid, this means that all
other forms and types of infectious and dangerous pathogens are known to
consist of DNA or RNA, however Prions are not, and this means then very unique
and special (Prusiner, 2000). The second is that certain prion syndromes can
lead to infectious, genetic and even sporadic neurodegenerative disorders
(Prusiner, 2000). The third is that prion diseases occur due to the build-up of
PrPsc which is composed of a unique conformation of PrPC.
The fourth and final is that PrPsc can have a wide range of
structures and conformations, and each of these different arrangements mean
that it has the ability to be able to specific to a certain disease (Prusiner,




Figure 1.  Recombinant PrP and PrPsc model. The top margin of the
figure highlights the a-helical arrangement of a hamster recombinant PrP
90-231, this shows the cellular isoform. The bottom part of the figure
showcases a credible model of the tertiary assembly of human PrPsc.

















Genetic prion
disease is known to consist of three specified pathological diseases known as
familial Creutzfeldt-Jakob disease (FCJD), Gerstmann-straussler-scheniker (GSS)
syndrome and familial fatal insomnia (FFI) (Moore RC et al,. 2001). The
following four points will help with the identification of genetic prion
disease. The first step is the sign of age-dependent neurologic symptoms such
as motoric incoordination, weaknesses, seizures, and muscle jerks (DeArmond SJ
et al, 1997). The second step is neuropathological outcomes that help highlight
and showcase degeneration that is clearly seen distributed and spread around
the cortex and deep nuclei of the brain, this is where amyloid plaque build-up
can be seen in vast quantities, at this stage antiprion protein and antibodies
begin to bind and join (Gambetti P et al, 2003). The third step to help with
the diagnosis of genetic prion disease is whether a prion protein gene (PRNP)
is present during the molecular genetic testing. And the fourth and final step
is whether the patient in question has a family history that is composed of a consistent
autosomal dominant inheritance. If all of these steps are met and positive in a
patient’s case, then they have a genetic prion disease (DeArmond SJ et al, 1997).

Figure 2. The image on the left highlights the PRNP gene polymorphisms and mutations,
in this example all the mutations are associated with CJD phonotype expect for
those in bold, the ones in bold are associated with GSS.  




Without the
involvement of a gene mutations or environmental variables, neurodegenerative
diseases are known as sporadic. These cases often occur by chance. However, 20%
these illness cases are known to be inherited, whereas 80% are sporadic (NHS,
2013). This trend can be clearly observed and analysed for neurodegenerative
diseases such as Creutzfeldt-Jakob disease (CJD), Alzheimer’s disease (AD) and
Parkinson’s disease (PD). The passing down from family members of the e4 allele
of apolipoprotein E is the prime genetic hazard for AD (Harold D et al., 2009).
Most if not all diseasing creating proteins have the potential of being able to
create prions, however most of the proteins are extinguished before they can
manifest themselves into such a variety quantity to seriously cause damage and
infectious prion disease, sporadic prion disease takes place as the proteins
transform into infectious prions through a self-propagating practice, this
though often has the outcome of showcasing a lost cause route where only a
handful of prions are cleared via protein degradation pathways (Annu Rev Genet.


Infectious prion
disease is known to only hold a value of 1% of all prion disease cases, however
the conditions and context of the transmission of these certain infectious
disorders are often dramatic (figure 3). As a result of the Fore people taking
part in ritualistic cannibalism, they are responsible for the spread and growth
of Kuru in New Guinea and industrial forms of cannibalism has caused and
created a new form of infectious prion disease known as Bovine spongiform
encephalopathy (BSE) and finally in main land Europe and some parts of north
America, people have contracted a new-version and type of Creutzfeldt-Jakob
diseases, this has took place due to the consumption of prion-contaminated beef
products (Will RG et al,. 1999).


Figure 3. The table on the left showcases the
pathogenic features of Prion disease.

The new evidence and
data of the new-type of Creutzfeldt-Jakob disease gives rise to the idea and
notice that it is caused by BSE prions that are known to be have been
transferred to humans (Will RG et al,. 1999). At this current moment in time,
there are no known particular nutritional intake practices that help scientists
distinguish patients suffering from this terrible disorder compared to the
average healthy individual, also this disorder known to be present in more in
young adults than any other age group, the prime reason as to why this is still
unclear in the present moment in time (Ghani AC et al,. 2000).


The most undeniable
piece if evidence and data highlighting that the new-type of Creutzfeldt-Jakob
disease is created by the BSE prions come from the knowledge and understanding
outlined from the technical study of mice expressing the bovine PrP transgene
(Scott MR et al,. 1999). The cultivation times, neuropathological qualities,
and patterns of PrPsc deposition looked at in the transgenic mice
showcased were exactly 100% the same even when the inoculate came from the
brains of cattle with the BSE prions or the new-type of Creutzfeldt-Jakob
disease (Scott MR et al,. 1999).




Over the course of
time, there has been a massive build of data which argues that neurodegenerative
diseases such as tauopathies, Alzheimer’s disease and Parkinson’s disease is
caused by prions (Stohr J, 2012). Through the advances in science and
technology, scientists understanding and knowledge of prion causing diseases
will help bring forward more effective and efficient treatment options. The
study of neurodegenerative diseases has given scientists a combination of great
developments with upsetting catastrophes, the understanding of AB peptide in
cerebrovascular amyloid and plaques is absolutely fundamental to the
understanding of AD pathogenesis (Watts JC et al, 2011). To this point in time,
there is no effective therapy or treatment option that actually stops a
neurodegenerative disease, and this is a massive failing and will require
addressing in order to progress in the future with the intention of curing neurodegenerative


By studying PrP
prions, scientists will have a greater understanding of how to create better
models and bioassays for AB, tau and a-synuclenin prions, unfortunately there
are no cultured cell systems for propagating AB prions have been made, however
these are amazing systems for propagating tau and a-synuclein prions are now
available. Now with greater understanding we know that tau prion is
manufactured by the use of tau fragments and complete size protein in vitro by
the exposure to arachidonic (Prusiner, 2000).


Most characteristics
and qualities of neurodegenerative diseases can be expounded by prions, the movement
and diversity of prions that can be found and located all over the central
nervous system give us a detailed clarification of the progression of neurodegenerative
diseases. By looking at various different types of neurodegenerative diseases,
the tauopathies gives us an extensive scale showcasing disorders with a direct
relationship highlighting clinical presentations and progression (Prusiner,




Unfortunately, with
the current study into prion protein disease, at this moment in time there is
no efficient, effective or permanent treatment available for neurodegenerative
disorders. However, levodopa can be used to enrich and soften the symptoms of
Parkinson’s disease, however levodopa is not a permanent therapy option as it
does not terminate the degeneration of Parkinson’s disease (Orr HT et al,


neurodegeneration in Parkinson’s disease is restrained to the substantia nigra,
using levodopa to treat and suppress the symptoms of Parkinson’s disease is
helpful however over time the use of levodopa does surpass as the Parkinson’s
becomes noncompliant with the replacement therapy option (Marsden CD et al,




The merging of past
and present studies, experiments and data collect on prion proteins
relationship with neurodegenerative disorders is extraordinary as it provides a
vast bank of knowledge upon which we can observe and analyse for greater understanding
for future studies and experiment into the topic. As many areas of prion
proteins have been explored and uncovered, this framework can be used in future
for more unforeseen breakthroughs through the future study of prions and