[37, 38] The original sCJD sub-classification system of Parchi et al. that recognized six sCJD subtypes (MM1/MV1, MM2c, MM2t, MV2, VV2 and VV1) has had to be modified to accommodate the growing number of cases recognized to contain both type 1

and type 2 PrPres in different or sometimes the same regions of the brain.[39, 40] Moreover, intensive surveillance and investigation of forms of human prion disease that lack PRNP mutation and known risk factors has identified another sporadic human prion disease, termed protease-sensitive prionopathy (VPSPr).[41] While intensively www.selleckchem.com/products/R788(Fostamatinib-disodium).html investigated, the etiology and diversity of the sporadic human prion diseases remain poorly understood. The prion hypothesis itself is of intrinsic interest. The expectation, implicit in the prion hypothesis, Temsirolimus order that in prion diseases the infectivity, the neurotoxicity and the strain-like properties of the agent (a prion) depend fundamentally on the structure and production of PrPSc presents a major challenge

to molecular biology. However, it is a challenge that is beginning to be met. If one defines a prion as a protein-based inheritance unit conferring a trait on the basis of a post-translational switch in conformation involving the acquisition of β-sheet structures and multimerization, then a group of yeast proteins, Ure2p, Sup35p, Rinq1p and HETs, are prions; associated with a variety of yeast cytoplasmic inheritance-based traits when present in their prion forms, URE3, PSI+, PIN+ and Het-s respectively.[4] These yeast and fungal

prions do not cause disease; instead they appear to represent an effective and common epigenetic mechanism for rapid cellular responses to environmental stress.[42, 43] Neither does this prion-like mechanism appear restricted to microbes. The Aplysia cytoplasmic polyadenylation element binding protein (CPEB), which is involved in long-term potentiation, is regulated by a PIK3C2G prion-like switch.[3, 44] Perhaps more controversially within neuropathology circles, the prion paradigm is being invoked as a way of understanding the behavior of proteins such as tau, α-synuclein, superoxide dismutase-1, TAR DNA-binding protein 43, FUS (Fused in Sarcoma) and huntingtin in their neuropathological context.[45-49] The analogy being drawn relates to: (i) a templated or seeded conversion mechanism; (ii) the possible existence of different molecular strain types; or (iii) the ways in which the proteopathy spreads within the nervous system.[50-53] The idea that neurodegenerative change in such diseases is non-cell autonomous, but instead represents the spread of molecular pathology, is of particular interest with respect to sporadic forms of disease.