Neuropathogenesis of Prion Disease

Louise Davidson; Richard Knight


Future Neurology. 2014;9(2):135-147. 

In This Article

Abstract and Introduction


Although much is known about prion diseases (characterized by a post-translational misfolding of the prion protein [PrP]) and their neuropathology and molecular pathology, the fundamental cause of illness, the basic neuropathogenesis, remains uncertain. There are three broad considerations discussed in this review: the possible loss of normal PrP function, the possible direct toxicity of the abnormally folded PrP and a harmful interaction between the normal and abnormal protein. In considering these possibilities, there are difficulties, including the facts that the relevant normal functions of the PrP are somewhat uncertain and that there are a number of possible toxic species of abnormal protein. In addition to the possible interactions of normal and abnormal PrP in prion disease, PrP may play a role in the neuropathogenesis of other diseases (such as Alzheimer's disease).


Prion diseases affect both animals and humans and occur in sporadic, acquired or inherited forms. Human examples include Creutzfeldt–Jakob Disease (CJD), Kuru, fatal familial insomnia and Gerstmann-Sträussler syndrome (GSS). CJD is subdivided into genetic, sporadic, iatrogenic and variant CJD.

They are essentially brain diseases with common neuropathological/molecular characteristics and potential transmissibility. The general neuropathological features are those of neuronal loss, astrocytic gliosis and spongiform change with deposition of aggregated abnormal prion protein (PrP).[1] In the most general terms, the common underlying molecular feature is the post-translational conformational change of a normally expressed protein, named PrPC, into a disease-associated form (PrPSc).[2] PrPC is a protease-sensitive, membrane-associated monomeric protein (with a glycosylphosphatidylinositol [GPI] anchor). PrPSc is generally characterized as more protease-resistant, with a higher β-sheet content and forms multimers, sometimes in the form of amyloid fibrils. These molecular characteristics are broadly similar to those found in other human neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease (although these involve different proteins).[3] However, one important distinctive feature of prion disease is the potential for natural transmission (between or within species).

There are potential terminological difficulties in discussing the basis of prion disease. PrPSc has been the most widely used designation for the disease-related form of PrP. However, it is a conceptual term that is arguably an umbrella covering a variety of molecular species. The name originates from the study of scrapie (hence the 'Sc' superscript) and some authors have preferred terms either more appropriate to other diseases (hence terms such as PrPCJD or PrPCWD), or ones with less specific disease connotations (such as PrPTSE or PrPd). In fact, what is most often studied is the protease-resistant core of disease-related PrP, usually designated PrPres. As a further complication, one paper has reported the detection of small amounts of insoluble, protease-resistant PrP in normal human brain and suggested that PrP differences between normal and prion disease brains may be quantitative rather than qualitative.[4] Finally, interest has centered on intermediate forms of PrP, between the normal PrPC and the abnormal aggregated, fibrillary protein found in disease tissue deposits.[3] Some authors have used the term PrP lethal (PrPL) to refer to a proposed neurotoxic form intermediate between, or separate from, PrPC and PrPSc.[5–7] In this article, 'PrP' is used to refer to the PrP in a general sense, with 'PrPSc' being used to denote disease-related PrP in the sense appropriate to the particular context and, certainly, it will sometimes denote PrPres.

In considering prion disease mechanisms, there are three relatively distinct areas. First, there is the nature of the infective agent (designated the 'prion') and infectivity; second, the mechanisms of transmission; and third, the actual neuropathogenic process. This review is concerned with the last of these.