Prion diseases have been the subject of much media interest recently due to the possibility of transmission of an infectious agent from cattle to humans. The nature of the infectious agent has not yet been definitively confirmed, however it seems clear that the PrP protein plays a key role and may itself be the sole component of the infectious agent (Prusiner, 1996).
The postulated mechanism of the disease is that PrP can exist in two (or possibly more) conformations. The normal conformation is that necessary for the functionality of the protein. In the alternative conformation, PrP-sc, the protein loses its functionality and becomes proteinease resistant. It also gains the ability to somehow catalyse the conversion of normal PrP into PrP-sc. PrP can also aggregate to form plaques and other structures characteristic of spongiform encephalopathies.
This idea of an infectious agent with no nucleic acid (a prion) is obviously a very exciting one. So much so, that relevant research elsewhere has perhaps been overlooked in the rush to understand the mechanism of the disease. In fact, the infectious nature of prion diseases, while obviously important from a public health point of view (and interesting from a scientific one), may be something of a red herring when it comes to understanding the progress of the disease and developing possible treatments. I would like to put forward the hypothesis here that, when looked at as inherited disorders, prion diseases show close similarity to another class of genetic disorders, the lysosomal storage diseases. I would therefore like to make the case that familial Creutzfeldt-Jacob disease (CJD) Fatal Familial Insomnia (FFI) and Gerstmann-Straussler-Scheinker disease (GSS) should in fact be classed with lysosomal storage diseases and that this classification would result in a useful cross-fertilization of ideas with researchers in that field.
Lysosomes are membrane-bound organelles responsible for turnover of cellular components. The lysosomal storage diseases (LSDs) are a group of inherited metabolic disorders in which one of the enzymes responsible for lysosomal degradation of intracellular components is non-functional, with the result that the substrate of the non-functional enzyme accumulates in the lysosomes (Neufeld, 1991). This leads to an increase in size and number of the lysosomes, eventually resulting in malfunction of the affected organ or organs. Examples include Tay-Sachs disease (GM2 ganglioside), Niemann-Pick disease (sphingomyelin) and Pompe disease (glycogen). There are currently 36 different types of LSD, some of which exhibit neurological involvement due to the effect of the cellular pathology on the nervous system. The course of each disease is determined by where the substrate accumulates fastest. For example glycogen accumulation is likely to primarily affect muscle tissue. All of the LSDs are serious conditions and most of them are fatal, resulting in death in infancy or early childhood.
At first glance there does not appear to be much in common between a group of diseases with a variety of symptoms centring on infancy and childhood, and the prion diseases which have a distinctive pathology which tends to become apparent later in life. For that reason perhaps, LSD's have tended to be the province of paediatric biochemists, and prion diseases the province of molecular biologists and neurologists. However, these apparent differences mask some important similarities.
CJD and other human variants of prion disease also exist as hereditary diseases. In these cases the amino acid sequence of the PrP protein presumably is such that it is predisposed to switch its conformation into the infectious prion form. The protease-resistant property of the prion form means that it cannot be digested by the lysosomal enzymes in the course of cell component turnover. Indeed, it has been suggested that the site of the PrP transformation is in fact the lysosome itself (Lazlo et al, 1992). Prion protein accumulates in the lysosomes, forming the structures observed in the brain tissue of affected individuals. It has been further suggested that the rupture of lysosomes and subsequent uncontrolled release of the lysosomal enzymes may result in cellular destruction which causes the spongiform phenotype.
The parallels between inherited prion disease and lysosomal storage disease then are striking. Both are inborn errors of metabolism in which a specific substrate accumulates in the lysosomes, leading to a cellular pathology which causes malfunction of the affected organ - in the case of prion diseases, the brain. Infectivity aside, the only difference is that in the case of LSDs as currently classified, the substrate accumulation is caused by an inherited enzyme deficiency, whereas in the case of prion disease it is caused by an inherited substrate defect. However in both cases the effect is exactly the same: an increase in the number and size of lysosomes leading to symptom development. The cellular pathology of human prion diseases is caused by lysosomal storage and so it should be included with the other lysosomal storage diseases. This would of course imply that the non-hereditary cases of CJD were the first described instance of acquired lysosomal storage disease.
The reason I have pursued this point is not an enthusiasm for semantics but because I believe that it is possible that research carried out to develop treatments for LSDs may have a bearing on developing treatments for prion diseases. This is because since the introduction of the concept of lysosomal storage diseases in 1965 there has been a great deal of research on the problems of developing treatments for these conditions - and some of this work this may be applicable to prion diseases.
It has been suggested that one theoretical treatment would be to develop a molecule which would preferentially bind to the PrP protein in a way that stabilised it and prevented conversion to the prion form (Prusiner, 1995) Other options might be to block the site on the prion molecule that allows it to convert normal PrP molecules to the prion conformation or alternatively an agent could be developed which would break down the protease resistant prion proteins.
In any of the above scenarios, such a therapeutic agent would need to be targeted on the membrane-bound lysosomes since this is the site of prion accumulation and probably conversion. This is a problem that researchers developing treatment for LSDs have been grappling with for some years. The mannose-6-phosphate receptor, for example, has been used to develop enzyme replacement therapy treatment for Gaucher disease (Barton et al, 1990), and has also been described for Pompe disease (Van der Ploeg et al, 1990). The strategy in both of these cases has been to develop a treatment for a particular LSD by introduction of the deficient enzyme using the lysosomal mannose-6-phosphate receptor to target it. It is possible that the same mechanism might be adapted to introduce a therapeutic for prion diseases.
There may be other avenues explored in lysosomal storage disease research that are of relevance to prion diseases - and vice versa. One common problem is that of the blood-brain barrier.
In conclusion, the superficial novelty of prion diseases has served to obscure their place in the mainstream of genetic disorders. I hope I have shown that there is scope for cross-fertilization of ideas and developments between the fields of prion disease and lysosomal storage disease research. Reclassifying prion diseases as lysosomal storage diseases would help to break down these artificial barriers and aid more productive research in both areas.
Lazlo, L., Lowe, J., Self, T., Kenwards, N., Landon, M., McBride, T., Farquhar, C., McConnell, I., Brown, J., Hope, J., Mayers, R.J. (1992) Lysosomes as key organelles in the pathogenesis of prion encephalopathies. Journal of Pathology 166:333-341
Neufeld, E.F. (1991) Lysosomal storage diseases Annual Review of Biochemistry 60:257-280
Prusiner, S. B. (1995) The Prion Diseases Scientific American 272: 70-77
Prusiner, S. B. (1996) Human Prion Diseases and Neurodegeneration in Prions, Prions, Prions, S.B. Prusiner, Ed Springer-Verlag, Berlin
Van der Ploeg, A.T., Kroos, M.A., Willemsen, R., Brons, N. H. C., Reuser, A.J.J. (1991) Intravenous administration of phosphorylated Acid alpha-glucosidase leads to uptake of enzyme in heart and skeletal muscle of mice. Journal of Clinical Investigation 87: 513-518
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