Disease Motifs
Investigating the Biomechanics of Disease
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Gerstmann Sträussler Scheinker Disease GSS

Three dimensional structure of Human Prion Protein HuPrP(90-231)
A graphical representation of the Human Prion Protein showing amino acid residues 90 to 231. This particular model (which can best be seen at the PDB by clicking on the image above) contains the Q212P mutation that is believed to increase the probablity of an individual developing Gerstmann Sträussler Scheinker Disease GSS.

Image courtesy of the RCSB PDB

Gerstmann Sträussler Scheinker syndrome (GSS) was first described in a large Austrian family, in which the affected individuals suffered a slow progressive cerebellar ataxia (unsteadiness and a lack of co-ordination) and cognitive decline, alongside this dementia there could also be spastic paraparesis (gradual weaken of the legs), however the characteristic of this disease was the widespread multi-centred amyloid plaques found in the brain. Using small studies which included a small number of affected patients, it was possible to study transmission using primates and rodents, and it was found that the most common causal polymorphism was seen to be the proline replaced by leucine at position 102 (P102L) but that transmission was successful in only 40% of cases. In further experiments in which transgenic mice were made to over express the mutant sequence (with P102L) the mice seemed to reproduce the symptoms of the disease.

There are other factors involved as there are reports that there are cases within the same family where there can be family members that suffer from the disease where the symptoms vary from the classical symptoms of GSS to the more typical symptoms of CJD. In another mutation (P105L) it has been noticed that in some families spastic paraparesis seemed to be the main symptom of the disease and the cerebellar dysfunction was not as prominent. At the post-mortem of the affected individuals the main sites of neurological damage appeared to be in the motor cortex and in the pyramidal tract while the cerebellum was relatively undamaged.

A less typical form of GSS is associated with a phenylalanine to serine change (F198S), in which the symptoms seem to be similar to Alzheimer's disease as there is the presence of neocortical neurofibrillary tangles. There is also a polymorphism, glutamine to arginine Q217R, which also leads to neurofibrillary tangles but with this polymorphism there is an accompanying degeneration in the substantia nigra which suggests not only some connection with Alzheimer's but also of Parkinson's disease.

The P105L and the Q217R mutations if inherited together seem to lead to plaques in the brain that will stain not only using anti-PrP antibodies but also with Aβ antibodies which bind the Aβ domain of the amyloid precursor protein which is associated with Alzheimer's disease.

There are other polymorphisms that are associated with GSS but P102L is the best studied example, and only very seldom is a case of GSS found where there is no mutation in the prion gene. Other polymorphisms are A117V, G131V, H187R, G202N, and Q212P.

GSS polymorphisms: P102L, P105L, A117V, G131V, H187R, F198S, D202N, Q212P and Q217R

The mutations that have been associated with GSS are illustrated in the diagram below. I have replaced the proline residues at positions 102 and 105 with leucine residues; the phenylalanine (F) at position 198 with serine (S); and the glutamine (Q) at position 217 with arginine (R).

The GSS Mutations P102L, P105L, F198S and Q217R

It is interesting to see that there seems to be some similarities with some of the symptoms of other illnesses such as Parkinson's and Alzheimer's disease. F198S leads to neocortical neurofibrillary tangles as does Q217R (as in Alzheimer's disease) and the latter also sees a degeneration in the substantia nigra (as occurs in Parkinson's disease).

If P105L and Q217R are inherited together there seems to be a build up of plaques in the brain which have similar properties to the amyloid precursor protein associated with Alzheimer's.

References and Resources

If any of the links below don't work please let me know. Some of the links are direct downloads to PDF. These might not start to download straight away and if this is the case just click 'Begin manual download'.
Find more about Gerstmann-Sträussler-Scheinker syndrome on Wikipedia Wikipedia - Gerstmann-Sträussler-Scheinker syndrome
Proceedings of the National Academy of Sciences Different patterns of truncated prion protein fragments correlate with distinct phenotypes in P102L Gerstmann-Sträussler-Scheinker disease.
Proc. Natl. Acad. Sci. USA Vol. 95, pp. 8322-8327, July 1998 Neurobiology
Proceedings of the National Academy of Sciences Prion protein preamyloid and amyloid deposits in Gerstmann-Sträussler-Scheinker disease, Indiana kindred.
G Giaccone, L Verga, O Bugiani, B Frangione, D Serban, S B Prusiner, M R Farlow, B Ghetti, and F Tagliavini
Istituto Neurologico Carlo Besta, Milan, Italy.
Proc Natl Acad Sci U S A. 1992 October 1; 89(19): 9349–9353.
Archives of Neurology Amyotrophy in Prion Diseases
Bradford B. Worrall, MD; Lewis P. Rowland, MD; Steven S.-M. Chin, MD, PhD; James A. Mastrianni, MD
Arch Neurol. 2000;57:33-38.
Research Collaboratory for Structural Bioinformatics (RCSB) Protein Data Bank PDB Structure of Prion at the PDB
I was having a few problems with this as I was hoping to take you directly into a model of the prion protein but this was not working too well. If you download Jmol you can interact with the protein.