Transmissible Spongiform Encephalopathies by r900ws


									               Transmissible Spongiform Encephalopathies

                    Andrew Stith Medical Virology 2006

       Transmissible Spongiform Encephalopathies (TSE’s) are diseases caused by

infectious protein particles. There are multiple forms of this disease each of which is

normally species specific for its infected host. The general TSE disease is characterized

by the refolding of the normal prion protein ( present in all animals and denominated

cellular prion protein or PrPc ), into an aberrantly folded form denoted as the disease

causing prion protein. It may also be labeled scrapie causing prion protein PrPsc as

scrapie was the first recognized prion disease. The infectious form of the prion protein is

thought to act as both the inducer and as a template to refold the normal PrPc into the

PrPsc form.

       Cellular PrPc is normally small, approximately 250-300 amino acids long and

consists of predominantly α-helices with small amounts of β-sheet secondary structures.

PrPc is susceptible to degradation by proteases, such as proteinase K. Single amino acid

polymorphisms in the genetic structure of PrPc can grant hosts resistance to some TSE’s

       Infectious PrPsc contains larger amounts of β-sheet secondary structure than

normal PrPc. It is only partially susceptible to proteinase K digestion in vitro, often only

being cleaved at the N or C termini. Although the PrPc structure has been solved for

many individual species, the structure of the infectious PrPsc has proven very difficult to

be determined due to its insolubility and highly hydrophobic character, as well as the

affinity of the PrPsc to form amyloidal aggregates.
       TSE’s exhibit several similar symptoms; however, the most prevalent symptom

characteristic of these diseases is the formation of vacuoles in the brain matter leading to

spongiosis of the brain causing neurodegenerative symptoms.

       The diseases discussed in this webpage include diseases of animals and humans.

Animal TSE’s include Scrapie which infects sheep and goats, Bovine Spongiform

Encephalopathy (BSE) which infects cattle and may cause Variant Creutzfeldt-Jakob (v-

CJD) disease in humans, and Chronic Wasting Disease (CWD) which infects cervids

such as deer, moose and elk. TSE Diseases in humans include multiple versions of

Creutzfeldt-Jakob disease (CJD), Kuru, Gerstmann-Straussler-Scheinker (GSS) and Fatal

Familial Insomnia (FFI).

Normal protein                                                         PrPsc
                                                                       Abnormal protein

 The abnormal prion protein is resistant to digestion with proteolytic enzymes which can
                 be visualized in a western blot assay as shown below.
a.     Western blot of brain homogenates from uninfected (lanes 1 and 2) and prion-infected (lanes 3 and 4) hamsters.

     Samples in lanes 2 and 4 were digested with a proteinase enzyme (proteinase K). Samples in lanes 1 and 3 were not

      treated. Under these conditions, PrPC in lanes 2 and 4 was completely degraded, whereas approximately 67 amino

       acids were digested from the PrPSc molecule to generate the smaller protease-resistant PrP molecule, PrP 27-30


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