The cell-to-cell transmission of the major pathogenic proteins of Parkinson's disease and Alzheimer's disease is reminiscent of the prion protein, which is defined as a proteinaceous infectious particle that causes human and animal transmissible spongiform encephalopathies.
These findings elucidate the molecular basis for a natural protective polymorphism in PrP and will enable the development of novel therapeutic strategies against prion diseases.
Conformational conversion of the cellular isoform of prion protein, designated PrP<sup>C</sup>, into the abnormally folded, amyloidogenic isoform, PrP<sup>Sc</sup>, is an essential pathogenic event in prion diseases.
Typically, the structural conversion occurs by misfolding of a single disease-associated protein, such as α-synuclein (αS) in Parkinson's disease, amyloid-β in Alzheimer's disease, and prion protein (PrP) in transmissible spongiform encephalopathies (TSEs).
Most cases of human prion disease occur from unknown reasons, and greater than 20 mutations in the prion protein (PrP) gene may lead to inherited prion disease.
Neuropatho- logical features of prion diseases include neuroinflammation featuring the infiltration of activated microglia in affected brain areas as well as the accumulation of an abnormal isoform of the cellular prion protein and neuronal loss.
Our results are the first to demonstrate in vivo, that the GPI-anchor signal sequence plays a fundamental role in the GPI-anchor composition, dictating the subcellular localization of a given protein and, in the case of PrPC, influencing the development of prion disease.
The C-terminally truncated Y145Stop variant of prion protein (PrP23-144), which is associated with heritable PrP cerebral amyloid angiopathy in humans and also capable of triggering a transmissible prion disease in mice, serves as a useful in vitro model for investigating the molecular and structural basis of amyloid strains and cross-seeding specificities.
Prion diseases are fatal neurodegenerative disorders related to the conformational alteration of the prion protein (PrP C) into a pathogenic and protease-resistant isoform (PrPSc).
The presence of abnormal, disease-related prion protein (PrP<sup>D</sup>) has recently been demonstrated by protein misfolding cyclic amplification (PMCA) in urine of patients affected with variant Creutzfeldt-Jakob disease (vCJD), a prion disease typically acquired from consumption of prion contaminated bovine meat.
Amino acids that differentiate ovine and deer normal host prion protein (PrP<sup>C</sup>) and associated with structural rigidity of the loop β2-α2 (S173N, N177T) appear to confer resistance to some prion diseases.
As amyloid formation is a key hallmark in prion pathogenesis, studying which segments in prion protein are involved in the amyloid formation can provide molecular details in the cross-species transmission barrier of prion diseases.
Cellular prion protein (PrP<sup>C</sup>) is a membrane-anchored glycoprotein representing the physiological counterpart of PrP scrapie (PrP<sup>Sc</sup>), which plays a pathogenetic role in prion diseases.
Compared to ND, t-PrP concentrations were significantly decreased in sCJD, iCJD and in genetic prion diseases associated with the three most common mutations E200K, V210I (associated with genetic CJD) and D178N-129M (associated with fatal familial insomnia).
Prion diseases in sheep and goats are called scrapie and belong to a group of transmissible spongiform encephalopathies (TSEs) caused by the abnormal misfolding of the prion protein encoded by the prion protein gene (PRNP).
To determine whether the increased susceptibility of bank voles to prion diseases can be attributed to the intrinsic nature of bank vole prion protein (PrP) or to host factors other than PrP, we produced transgenic mice overexpressing bank vole PrP.
Case-controlled studies in several species, including humans and cattle, indicated a potent association of prion protein gene (<i>PRNP</i>) polymorphisms in the progression of prion disease.
Although the unifying hallmark of prion diseases is CNS neurodegeneration caused by conformational corruption of host prion protein (PrP) to its infective counterpart, contagious transmission of chronic wasting disease (CWD) results from shedding of prions produced at high titers in the periphery of diseased cervids.
Here, we explore recent advances in prion disease research, from the function of the cellular prion protein to the dysfunction triggering neurotoxicity, as well as mechanisms underlying prion spread between cells.
Prion disease is unique in that the natively folded prion protein forms diverse misfolded aggregates with distinct molecular conformations (strains), which underlie different disease phenotypes.