The accumulation and spread of prion-like proteins is a key feature of neurodegenerative diseases (NDs) such as Alzheimer's disease, Parkinson's disease, or Amyotrophic Lateral Sclerosis. In a process known as 'seeding', prion-like proteins such as amyloid beta, microtubule-associated protein tau, α-synuclein, silence superoxide dismutase 1, or transactive response DNA-binding protein 43 kDa, propagate their misfolded conformations by transforming their respective soluble monomers into fibrils. Cellular and molecular evidence of prion-like propagation in NDs, the clinical relevance of their 'seeding' capacities, and their levels of contribution towards disease progression have been intensively studied over recent years. This review unpacks the cyclic prion-like propagation in cells including factors of aggregate internalization, endo-lysosomal leaking, aggregate degradation, and secretion. Debates on the importance of the role of prion-like protein aggregates in NDs, whether causal or consequent, are also discussed. Applications lead to a greater understanding of ND pathogenesis and increased potential for therapeutic strategies.
Humans ; Prions ; Neurodegenerative Diseases/pathology* ; Amyloid beta-Peptides ; Alzheimer Disease ; alpha-Synuclein ; tau Proteins ; Parkinson Disease

Human genetic prion diseases (gPrDs) are directly associated with mutations and insertions in the PRNP (Prion Protein) gene. We collected and analyzed the data of 218 Chinese gPrD patients identified between Jan 2006 and June 2020. Nineteen different subtypes were identified and gPrDs accounted for 10.9% of all diagnosed PrDs within the same period. Some subtypes of gPrDs showed a degree of geographic association. The age at onset of Chinese gPrDs peaked in the 50-59 year group. Gerstmann-Sträussler-Scheinker syndrome (GSS) and fatal familial insomnia (FFI) cases usually displayed clinical symptoms earlier than genetic Creutzfeldt-Jakob disease (gCJD) patients with point mutations. A family history was more frequently recalled in P105L GSS and D178N FFI patients than T188K and E200K patients. None of the E196A gCJD patients reported a family history. The gCJD cases with point mutations always developed clinical manifestations typical of sporadic CJD (sCJD). EEG examination was not sensitive for gPrDs. sCJD-associated abnormalities on MRI were found in high proportions of GSS and gCJD patients. CSF 14-3-3 positivity was frequently detected in gCJD patients. Increased CSF tau was found in more than half of FFI and T188K gCJD cases, and an even higher proportion of E196A and E200K gCJD patients. 63.6% of P105L GSS cases showed a positive reaction in cerebrospinal fluid RT-QuIC. GSS and FFI cases had longer durations than most subtypes of gCJD. This is one of the largest studies of gPrDs in East Asians, and the illness profile of Chinese gPrDs is clearly distinct. Extremely high proportions of T188K and E196A occur among Chinese gPrDs; these mutations are rarely reported in Caucasians and Japanese.
14-3-3 Proteins/cerebrospinal fluid* ; China ; Creutzfeldt-Jakob Syndrome/genetics* ; Humans ; Mutation/genetics* ; Prion Diseases/genetics* ; Prion Proteins/genetics* ; Prions/genetics* ; tau Proteins/cerebrospinal fluid*

Genetic prion diseases account for about 10-15% of all cases of human prion disease and are caused by mutations in the prion protein gene. Gerstmann-Sträussler-Scheinker (GSS) disease is a rare genetic prion disease, which is characterized by slowly progressive cerebellar ataxia and the occurrence of cognitive decline in the later stage. P102L is the most common mutation in GSS. We report a patient with a P102L mutation that initially manifested as rapidly progressive dementia without cerebellar symptoms.
Cerebellar Ataxia ; Creutzfeldt-Jakob Syndrome ; Dementia ; Gerstmann-Straussler-Scheinker Disease ; Humans ; Prion Diseases ; Prions

Amyloid fibril formation has been implicated in the pathogenesis of neurodegenerative diseases. Fibrillation generates numerous conformers. Presumably, the conformers may possess specific biological properties, thus providing a biochemical framework for strains of prions. However, the precise relationship between various fibril conformers and their pathogenic functions has not been determined because of limited accessibility to adequate amounts of fibrils from tissue samples. α-Synuclein is one such protein, and it has been implicated in Parkinson disease. Using a technique known as protein misfolding cyclic amplification, originally developed for amplifying prions, we established a procedure through which the amplification of α-synuclein fibrils is possible. With a trace amount of seeds, we succeeded in amplifying α-synuclein fibrils. The replication of the seeds was faithful in terms of conformation even after multiple rounds of cyclic amplification. Moreover, two transgenic mouse strains each representing a distinct synucleinopathy were used to investigate different conformers by using this technique. The amplified α-synuclein fibrils derived from the tissue extracts of these two strains led to the production of two different fibril conformers with distinct proteinase K digestion profiles. Together, our results demonstrated that a trace amount of α-synuclein fibrils in tissue extracts could be amplified with their conformations conserved. This procedure should be useful in amplifying α-synuclein fibrils from the brains and body fluids of patients afflicted with synucleinopathies and may serve as a potential diagnostic tool for Parkinson disease and other synucleinopathies.
Amyloid ; Animals ; Body Fluids ; Brain ; Digestion ; Endopeptidase K ; Humans ; Mice ; Mice, Transgenic ; Neurodegenerative Diseases ; Parkinson Disease ; Prions ; Tissue Extracts

ALS is a fatal adult-onset motor neuron disease. Motor neurons in the cortex, brain stem and spinal cord gradually degenerate in ALS patients, and most ALS patients die within 3~5 years of disease onset due to respiratory failure. The major pathological hallmark of ALS is abnormal accumulation of protein inclusions containing TDP-43, FUS or SOD1 protein. Moreover, the focality of clinical onset and regional spreading of neurodegeneration are typical features of ALS. These clinical data indicate that neurodegeneration in ALS is an orderly propagating process, which seems to share the signature of a seeded self-propagation with pathogenic prion proteins. In vitro and cell line experimental evidence suggests that SOD1, TDP-43 and FUS form insoluble fibrillar aggregates. Notably, these protein fibrillar aggregates can act as seeds to trigger the aggregation of native counterparts. Collectively, a self-propagation mechanism similar to prion replication and spreading may underlie the pathology of ALS. In this review, we will briefly summarize recent evidence to support the prion-like properties of major ALS-associated proteins and discuss the possible therapeutic strategies for ALS based on a prion-like mechanism.
Amyotrophic Lateral Sclerosis* ; Brain Stem ; Cell Line ; Humans ; Motor Neuron Disease ; Motor Neurons ; Pathology ; Prions ; Respiratory Insufficiency ; Spinal Cord

Scrapie is diagnosed antemortem in sheep by detecting misfolded isoforms of prion protein (PrP(Sc)) in lymphoid follicles of the rectal mucosa and nictitating membranes. Assay sensitivity is limited if (a) the biopsy is collected early during disease development, (b) an insufficient number of follicles is collected, or (c) peripheral accumulation of PrP(Sc) is reduced or delayed. A blood test would be convenient for mass live animal scrapie testing. Currently approved techniques, however, have their own detection limits. Novel detection methods may soon offer a non-animal-based, rapid platform with detection sensitivities that rival the prion bioassay. In anticipation, we sought to determine if diseased animals could be routinely identified with a bioassay using B lymphocytes isolated from blood sample volumes commonly collected for diagnostic purposes in small ruminants. Scrapie transmission was detected in five of six recipient lambs intravenously transfused with B lymphocytes isolated from 5~10 mL of blood from a naturally scrapie-infected sheep. Additionally, scrapie transmission was observed in 18 ovinized transgenic Tg338 mice intracerebrally inoculated with B lymphocytes isolated from 5~10 mL of blood from two naturally scrapie-infected sheep. Based on our findings, we anticipate that these blood sample volumes should be of diagnostic value.
Animals ; B-Lymphocytes/*pathology ; Biological Assay/*veterinary ; Mice ; Mice, Transgenic ; Prions/*blood ; Scrapie/blood/*diagnosis/transmission ; Sheep

Human prion diseases are fatal neurodegenerative disorders that are characterized by spongiform changes, astrogliosis, and the accumulation of an abnormal prion protein (PrP(Sc)). Approximately 10%-15% of human prion diseases are familial variants that are caused by pathogenic mutations in the prion protein gene (PRNP). Point mutations or the insertions of one or more copies of a 24 bp repeat are associated with familial human prion diseases including familial Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker syndrome, and fatal familial insomnia. These mutations vary significantly in frequency between countries. Here, we compare the frequency of PRNP mutations between European countries and East Asians. Associations between single nucleotide polymorphisms (SNPs) of several candidate genes including PRNP and CJD have been reported. The SNP of PRNP at codon 129 has been shown to be associated with sporadic, iatrogenic, and variant CJD. The SNPs of several genes other than PRNP have been showed contradictory results. Case-control studies and genome-wide association studies have also been performed to identify candidate genes correlated with variant and/or sporadic CJD. This review provides a general overview of the genetic mutations and polymorphisms that have been analyzed in association with human prion diseases to date.
Europe ; Far East ; Humans ; Mutation ; Polymorphism, Single Nucleotide ; Prion Diseases/epidemiology/*genetics ; Prions/*genetics

Misfolded isoform of prion protein (PrP), termed scrapie PrP (PrP(Sc)), tends to aggregate into various fibril forms. Previously, we reported various conditions that affect aggregation of recombinant PrP into amyloids. Because amyloidogenesis of PrP is closely associated with transmissible spongiform encephalopathies such as Creutzfeldt-Jakob disease in humans, we investigated infectivity of recombinant PrP amyloids generated in vitro. Using cultured cell lines which overexpress cellular PrP of different species, we measured the level of de novo synthesized PrP(Sc) in cells inoculated with recombinant mouse PrP amyloids. While PrP-overexpressing cells were susceptible to mouse-adapted scrapie prions used as the positive control, demonstrating the species barrier effect, infection with amyloids made of truncated recombinant PrP (PrP[89-230]) failed to form and propagate PrP(Sc) even in the cells that express mouse cellular PrP. This suggests that infectivity of PrP amyloids generated in vitro is different from that of natural prions. Recombinant PrP (89-230) amyloids tested in the current study retain no or a minute level, if any, of prion infectivity.
Animals ; Cell Line ; Kidney/*metabolism/*pathology ; Mice ; PrPSc Proteins/*metabolism ; Prion Diseases/*metabolism/*pathology ; Prions/*metabolism ; Rabbits ; Recombinant Proteins/*metabolism ; Up-Regulation

Cellular prion protein, a membrane protein, is expressed in all mammals. Prion protein is also found in human blood as an anchorless protein, and this protein form is one of the many potential sources of misfolded prion protein replication during transmission. Many studies have suggested that beta-amyloid1-42 oligomer causes neurotoxicity associated with Alzheimer's disease, which is mediated by the prion protein that acts as a receptor and regulates the hippocampal potentiation. The prevention of the binding of these proteins has been proposed as a possible preventative treatment for Alzheimer's disease; therefore, a greater understanding of the binding hot-spots between the two molecules is necessary. In this study, the epitope mapping immunoassay was employed to characterize binding epitopes within the prion protein and complementary epitopes in beta-amyloid. Residues 23-39 and 93-119 in the prion protein were involved in binding to beta-amyloid1-40 and 1-42, and monomers of this protein interacted with prion protein residues 93-113 and 123-166. Furthermore, beta-amyloid antibodies against the C-terminus detected bound beta-amyloid1-42 at residues 23-40, 104-122 and 159-175. beta-Amyloid epitopes necessary for the interaction with prion protein were not determined. In conclusion, charged clusters and hydrophobic regions of the prion protein were involved in binding to beta-amyloid1-40 and 1-42. The 3D structure appears to be necessary for beta-amyloid to interact with prion protein. In the future, these binding sites may be utilized for 3D structure modeling, as well as for the pharmaceutical intervention of Alzheimer's disease.
Amyloid beta-Peptides/*metabolism ; Electrophoresis ; Enzyme-Linked Immunosorbent Assay ; *Epitope Mapping ; Epitopes/*metabolism ; Humans ; *Immunoassay ; Prions/*metabolism ; Protein Binding ; Recombinant Proteins/metabolism

Chronic wasting disease (CWD) is classified as a transmissible spongiform encephalopathy or prion disease that affects cervids. CWD has been reported in 15 US states, two Canadian provinces, and in imported elk on several farms in Korea. This study was conducted to examine the molecular biological and pathogenic characteristics of a CWD-associated prion isolated in Korea. The epidemiological origin of this pathogen was also determined. Homozygous TgElk mice were infected with a CWD-affected elk brain pool prepared from the brain of an imported Canadian elk. We measured the incubation time of the pathogen, neuropathological changes by immunohistochemical staining, the pattern(s) of scrapie prion protein (PrPSc) deposition, and PrPSc protein profiles by Western blotting. We found that TgElk mice infected with brain homogenate from the elk suffering from CWD showed incubation times, vacuolar degeneration, and PrPSc accumulation similar to those previously reported in the literature. Our results suggest that homozygous TgElk mice efficiently transmit CWD with short incubation times and that this animal can serve a valuable research model and reliable in vivo diagnostic tool.
Animals ; Brain/*pathology ; *Deer ; Female ; Genotype ; Mice ; Mice, Transgenic ; Prions ; Republic of Korea/epidemiology ; Wasting Disease, Chronic/epidemiology/*pathology/transmission