Prion [JOURNAL]
Sun
200 papers
Effects of peptidyl-prolyl isomerase 1 depletion in animal models of prion diseases.
Legname G, Virgilio T, Bistaffa E … +8 more , De Luca CMG, Catania M, Zago P, Isopi E, Campagnani I, Tagliavini F, Giaccone G, Moda F
Prion · 2018 Mar · PMID 29676205 · Full text
Pin1 is a peptidyl-prolyl isomerase that induces the cis-trans conversion of specific Ser/Thr-Pro peptide bonds in phosphorylated proteins, leading to conformational changes through which Pin1 regulates protein stability...
Pin1 is a peptidyl-prolyl isomerase that induces the cis-trans conversion of specific Ser/Thr-Pro peptide bonds in phosphorylated proteins, leading to conformational changes through which Pin1 regulates protein stability and activity. Since down-regulation of Pin1 has been described in several neurodegenerative disorders, including Alzheimer's Disease (AD), Parkinson's Disease (PD) and Huntington's Disease (HD), we investigated its potential role in prion diseases. Animals generated on wild-type (Pin1), hemizygous (Pin1) or knock-out (Pin1) background for Pin1 were experimentally infected with RML prions. The study indicates that, neither the total depletion nor reduced levels of Pin1 significantly altered the clinical and neuropathological features of the disease.
Decrease of RyR2 in the prion infected cell line and in the brains of the scrapie infected mice models and the patients of human prion diseases.
Shi Q, Li JL, Ma Y … +7 more , Gao LP, Xiao K, Wang J, Zhou W, Chen C, Guo YJ, Dong XP
Prion · 2018 · PMID 29676187 · Full text
The levels of ryanodine receptors (RyRs) are usually increased in the brains of human Alzheimer disease (AD) and AD animal models. To evaluate the underlying alteration of brain RyRs in prion disease, scrapie infected ce...
The levels of ryanodine receptors (RyRs) are usually increased in the brains of human Alzheimer disease (AD) and AD animal models. To evaluate the underlying alteration of brain RyRs in prion disease, scrapie infected cell line SMB-S15 and its infected mice were tested. RyR2 specific Western blots revealed markedly decreased RyR2 levels both in the cells and in the brains of infected mice. Assays of the brain samples of other scrapie (agents 139A and ME7) infected mice collected at different time-points during incubation period showed time-dependent decreases of RyR2. Immunofluorescent assays (IFA) verified that the expression of RyR2 locates predominantly in cytoplasm of SMB cells and overlapped with the neurons in the brain slices of mice. Furthermore, significant down-regulation of RyR2 was also detected in the postmortem cortical brains of the patients of various types of human prion diseases, including sporadic Creutzfeldt-Jakob disease (sCJD), fatal familial insomnia (FFI) and G114V-genetic CJD. Our data here propose the evidences of remarkably decreased brain RyR2 at terminal stages of both human prion diseases and prion infected rodent models. It also highlights that the therapeutic strategy with antagonist of RyRs in AD may not be suitable for prion disease.
Role of Prion protein-EGFR multimolecular complex during neuronal differentiation of human dental pulp-derived stem cells.
Martellucci S, Manganelli V, Santacroce C … +4 more , Santilli F, Piccoli L, Sorice M, Mattei V
Prion · 2018 Mar · PMID 29644924 · Full text
Cellular prion protein (PrP) is expressed in a wide variety of stem cells in which regulates their self-renewal as well as differentiation potential. In this study we investigated the presence of PrP in human dental pulp...
Cellular prion protein (PrP) is expressed in a wide variety of stem cells in which regulates their self-renewal as well as differentiation potential. In this study we investigated the presence of PrP in human dental pulp-derived stem cells (hDPSCs) and its role in neuronal differentiation process. We show that hDPSCs expresses early PrP at low concentration and its expression increases after two weeks of treatment with EGF/bFGF. Then, we analyzed the association of PrP with gangliosides and EGF receptor (EGF-R) during neuronal differentiation process. PrP associates constitutively with GM2 in control hDPSCs and with GD3 only after neuronal differentiation. Otherwise, EGF-R associates weakly in control hDPSCs and more markedly after neuronal differentiation. To analyze the functional role of PrP in the signal pathway mediated by EGF/EGF-R, a siRNA PrP was applied to ablate PrP and its function. The treatment with siRNA PrP significantly prevented Akt and ERK1/2 phosphorylation induced by EGF. Moreover, siRNA PrP treatment significantly prevented neuronal-specific antigens expression induced by EGF/bFGF, indicating that cellular prion protein is essential for EGF/bFGF-induced hDPSCs differentiation. These results suggest that PrP interact with EGF-R within lipid rafts, playing a role in the multimolecular signaling complexes involved in hDPSCs neuronal differentiation.
THERPA: A small molecule database related to prion protein regulation and prion diseases progression.
Lee SM, Lee W, Lee YS … +4 more , Yoo JS, Park SJ, Kim H, Kim SY
Prion · 2018 Mar · PMID 29633896 · Full text
Prion diseases are fatal neurodegenerative disorders that affect humans and animals. Although various small molecules have been evaluated for application in the treatment of prion diseases, none have been shown to be eff...
Prion diseases are fatal neurodegenerative disorders that affect humans and animals. Although various small molecules have been evaluated for application in the treatment of prion diseases, none have been shown to be efficacious. Expanding our knowledge of these molecules is important for understanding of the complex mechanisms of prion diseases. To improve access to the scattered information on small molecules related to prion diseases, we built a database of therapeutic molecules associated with prion diseases (THERPA, therpa.pythonanywhere.com). THERPA includes 119 small molecules and their 283 relationships with prion diseases. THERPA is an interactive visual database and useful for improving search efficiency which can help researchers identify intrinsic small molecules that can be used for developing therapeutics for prion diseases.
Prolonged follicular helper T cell responses in ME7 scrapie-infected mice.
Kim S, Han S, Kim T … +4 more , Nam J, Kim YS, Choi EK, Kim MY
Prion · 2018 Mar · PMID 29617174 · Full text
We previously reported that mice intracerebrally inoculated with the mouse-adapted scrapie strain ME7 have markedly diminished T zones in the spleen due to the decreased expression of CCL19 and CCL21. In addition, follic...
We previously reported that mice intracerebrally inoculated with the mouse-adapted scrapie strain ME7 have markedly diminished T zones in the spleen due to the decreased expression of CCL19 and CCL21. In addition, follicular dendritic cell networks in germinal centers were larger in ME7-infected spleens compared to uninfected spleens. As an extension of that study, we set out to determine how ME7 infection affects spleen structure and follicular helper T (Tfh) cell responses in mice. For this study, mice were intraperitoneally inoculated with brain homogenate of the ME7 inoculum and spleens were analyzed 50, 130, and 200 days after inoculation and compared with those from uninfected mice. The result showed that ME7- infected mice had increased Tfh cell responses which were maintained until end-stage prion disease. Although CD4 T cells decreased in white pulps, they increased in germinal centers, and expressed higher levels of the Tfh-related genes, such as Bcl6, Il21, Cxcr5, Icos, and Pdcd1. In addition, ME7-infected spleens had increased numbers of CD4 memory T cells. These data indicate that although ME7 infection led to impaired splenic white pulp structure, CD4 memory T cells were increased and Tfh cell responses were required and prolonged to provide help for the replication and accumulation of pathogenic prion protein in germinal centers.
A Chinese patient of P102L Gerstmann-Sträussler-Scheinker disease contains three other disease-associated mutations in SYNE1.
Wang J, Xiao K, Zhou W … +4 more , Gao C, Chen C, Shi Q, Dong XP
Prion · 2018 Mar · PMID 29509064 · Full text
Gerstmann-Sträussler-Scheinker disease (GSS) with the P102L mutation in PRNP gene is characterized with progressive cerebellar dysfunction clinically and PrP plaques neurologically. Due to the cerebellar ataxia in the ea...
Gerstmann-Sträussler-Scheinker disease (GSS) with the P102L mutation in PRNP gene is characterized with progressive cerebellar dysfunction clinically and PrP plaques neurologically. Due to the cerebellar ataxia in the early stage, GSS P102L is often misdiagnosed as other neurodegenerative disorders. We presented here a 49-year-old female patient with proven P102L PRNP mutation, and three heterologous mutations in hereditary ataxias associated gene SYNE1, including p.V3643L, p.M3376V and p.T2860A. The patient appeared progressive unsteady gait in early stage and developed the Creutzfeldt-Jacob disease (CJD) - associated clinical manifestations, including progressive dementia, myoclonus, pyramidal and extrapyramidal signs. She is still alive but with akinetic mutism 21 months after onset. Observation of intense signal changes in cortical regions (cortical ribboning) in diffusion weighted imaging (DWI) MRI scanning and positive protein 14-3-3 in cerebrospinal fluid (CSF) proposed the diagnosis of sporadic CJD. The final diagnosis of P102L GSS was made after PRNP sequencing.
Design, implementation, and interpretation of amplification studies for prion detection.
Haley NJ, Richt JA, Davenport KA … +7 more , Henderson DM, Hoover EA, Manca M, Caughey B, Marthaler D, Bartz J, Gilch S
Prion · 2018 Mar · PMID 29468946 · Full text
Amplification assays for transmissible spongiform encephalopathies have been in development for close to 15 years, with critical implications for the postmortem and antemortem diagnosis of human and animal prion diseases...
Amplification assays for transmissible spongiform encephalopathies have been in development for close to 15 years, with critical implications for the postmortem and antemortem diagnosis of human and animal prion diseases. Little has been published regarding the structured development, implementation and interpretation of experiments making use of protein misfolding cyclic amplification (PMCA) and real time quaking-induced conversion (RT-QuIC), and our goal with this Perspectives manuscript is to offer a framework which might allow for more efficient expansion of pilot studies into diagnostic trials in both human and animal subjects. This framework is made up of approaches common to diagnostic medicine, including a thorough understanding of analytical and diagnostic sensitivity and specificity, an a priori development of amplification strategy, and an effective experimental design. It is our hope that a structured framework for prion amplification assays will benefit not only experiments seeking to sensitively detect naturally-occurring cases of prion diseases and describe the pathogenesis of TSEs, but ultimately assist with future endeavors seeking to use these methods more broadly for other protein misfolding disorders, including Alzheimer's and Parkinson's disease.
Chronic wasting disease management in ranched elk using rectal biopsy testing.
Haley NJ, Henderson DM, Wycoff S … +6 more , Tennant J, Hoover EA, Love D, Kline E, Lehmkuhl A, Thomsen B
Prion · 2018 Mar · PMID 29424295 · Full text
Chronic wasting disease (CWD) is a transmissible spongiform encephalopathy (TSE) affecting members of the cervid species, and is one of the few TSEs with an expanding geographic range. Diagnostic limitations, efficient t...
Chronic wasting disease (CWD) is a transmissible spongiform encephalopathy (TSE) affecting members of the cervid species, and is one of the few TSEs with an expanding geographic range. Diagnostic limitations, efficient transmission, and the movement of infected animals are important contributing factors in the ongoing spread of disease. Managing CWD in affected populations has proven difficult, relying on population reduction in the case of wild deer and elk, or quarantine and depopulation in farmed cervids. In the present study, we evaluated the effectiveness of managing endemic CWD in a closed elk herd using antemortem sampling combined with both conventional and experimental diagnostic testing, and selective, targeted culling of infected animals. We hypothesized that the real-time quaking-induced conversion (RT-QuIC) assay, a developing amplification assay, would offer greater detection capabilities over immunohistochemistry (IHC) in the identification of infected animals using recto-anal mucosa associated lymphoid tissue (RAMALT). We further sought to develop a better understanding of CWD epidemiology in elk with various PRNP alleles, and predicted that CWD prevalence would decrease with targeted culling. We found that RT-QuIC identified significantly more CWD-positive animals than IHC using RAMALT tissues (121 vs. 86, respectively, out of 553 unique animals), and that longstanding disease presence was associated with an increasing frequency of less susceptible PRNP alleles. Prevalence of CWD increased significantly over the first two years of the study, implying that refinements in our management strategy are necessary to reduce the prevalence of CWD in this herd.
Case Report: A patient with spinocerebellar ataxia type 31 and sporadic Creutzfeldt-Jakob disease.
Saito N, Ishihara T, Kasuga K … +6 more , Nishida M, Ishiguro T, Nozaki H, Shimohata T, Onodera O, Nishizawa M
Prion · 2018 Mar · PMID 29411683 · Full text
We report a Japanese patient with spinocerebellar ataxia type 31 (SCA31) and sporadic Creutzfeldt-Jakob disease (sCJD). A 52-year-old man developed progressive cognitive impairment after the appearance of cerebellar symp...
We report a Japanese patient with spinocerebellar ataxia type 31 (SCA31) and sporadic Creutzfeldt-Jakob disease (sCJD). A 52-year-old man developed progressive cognitive impairment after the appearance of cerebellar symptoms. Brain MR diffusion-weighted imaging (DWI) demonstrated a slowly expanding hyperintense lesion in the cerebral cortex. The patient was finally diagnosed as having both SCA31 and sCJD by identification of genetic mutations and by real-time quaking-induced conversion (RT-QUIC) analysis of the cerebrospinal fluid (CSF), respectively. Here, we report the clinical details of this rare combined case, with particular reference to the association between prion protein and the early onset of SCA31.
Genetic effects of PRNP gene insertion/deletion (indel) on phenotypic traits in sheep.
Li J, Erdenee S, Zhang S … +9 more , Wei Z, Zhang M, Jin Y, Wu H, Chen H, Sun X, Xu H, Cai Y, Lan X
Prion · 2018 Jan · PMID 29394137 · Full text
Prion protein (PRNP) gene is well known for affecting mammal transmissible spongiform encephalopathies (TSE), and is also reported to regulate phenotypic traits (e.g. growth traits) in healthy ruminants. To identify the...
Prion protein (PRNP) gene is well known for affecting mammal transmissible spongiform encephalopathies (TSE), and is also reported to regulate phenotypic traits (e.g. growth traits) in healthy ruminants. To identify the insertion/deletion (indel) variations of the PRNP gene and evaluate their effects on growth traits, 768 healthy individuals from five sheep breeds located in China and Mongolia were identified and analyzed. Herein, four novel indel polymorphisms, namely, Intron-1-insertion-7bp (I1-7bp), Intron-2-insertion-15bp (I2-15bp), Intron-2-insertion-19bp (I2-19bp), and 3' UTR-insertion-7bp (3' UTR-7bp), were found in the sheep PRNP gene. In five analyzed breeds, the minor allelic frequencies (MAF) of the above indels were in the range of 0.008 to 0.986 (I1-7bp), 0.113 to 0.336 (I2-15bp), 0.281 to 0.510 (I2-19bp), and 0.040 to 0.238 (3' UTR-7bp). Additionally, there were 15 haplotypes and the haplotype 'I-D-D-D' had the highest frequency, which varied from 0.464 to 0.629 in five breeds. Moreover, association analysis revealed that all novel indel polymorphisms were significantly associated with 13 different growth traits (P < 0.05). Particularly, the influences of I2-15bp on chest width (P = 0.001) in Small Tail Han sheep (ewe), 3' UTR-7bp on chest circumference (P = 0.003) in Hu sheep, and I2-19bp on tail length (P = 0.001) in Tong sheep, were highly significant (P < 0.01). These findings may be a further step toward the detection of indel-based typing within and across sheep breeds, and of promising target loci for accelerating the progress of marker-assisted selection in sheep breeding.
Impaired transport of intrinsically disordered proteins through the Sec61 and SecY translocon; implications for prion diseases.
Jung S, Tatzelt J
Prion · 2018 Mar · PMID 29388511 · Full text
The prion protein (PrP) is composed of two major domains of similar size. The structured C-terminal domain contains three alpha-helical regions and a short two-stranded beta-sheet, while the N-terminal domain is intrinsi...
The prion protein (PrP) is composed of two major domains of similar size. The structured C-terminal domain contains three alpha-helical regions and a short two-stranded beta-sheet, while the N-terminal domain is intrinsically disordered. The analysis of PrP mutants with deletions in the C-terminal globular domain provided the first hint that intrinsically disordered domains are inefficiently transported into the endoplasmic reticulum through the Sec61 translocon. Interestingly, C-terminally truncated PrP mutants have been linked to inherited prion disease in humans and are characterized by inefficient ER import and the formation of neurotoxic PrP conformers. In a recent study we found that the Sec61 translocon in eukaryotic cells as well as the SecY translocon in bacteria is inherently deficient in translocating intrinsically disordered proteins. Moreover, our results suggest that translocon-associated components in eukaryotic cells enable the Sec61 complex to transport secretory proteins with extended unstructured domains such as PrP and shadoo.
Behind the potential evolution towards prion resistant species.
Fernández-Borges N, Eraña H, Castilla J
Prion · 2018 Mar · PMID 29388474 · Full text
Historically, the observation of naturally occurring cases of prion disease led to the classification of different susceptibility grades and to the designation of prion resistant species. However, the development of high...
Historically, the observation of naturally occurring cases of prion disease led to the classification of different susceptibility grades and to the designation of prion resistant species. However, the development of highly efficient in vitro prion propagation systems and the generation of ad hoc transgenic models allowed determining that leporidae and equidae families have been erroneously considered resistant to prion infection. On the contrary, similar approaches revealed an unexpected high level of resistance of the canidae family. In PLoS Pathogens [ 1 ], we describe experiments directed toward elucidating which are the determinants of the alleged prion resistance of this family. Studies based on the sequence of the canine prion protein coupled with structural in silico analysis identified a key residue probably implicated in this resistance. Cell and brain-based PMCA highlighted that the presence of aspartic or glutamic acid at codon 163 of the canid PrP, strongly inhibits prion replication in vitro. Transgenic animals carrying this substitution in mouse PrP were resistant to prion infection after intracerebral challenge with different mouse prion strains. The confirmation of the importance of this substitution and its exclusivity in this family, suggests it could have been evolutionarily favored, due to their diet based on carrion and small ruminants.
Wernicke-Korsakoff syndrome as a rare phenotype of sporadic Creutzfeldt-Jakob disease.
Bielewicz J, Szczepańska-Szerej A, Ogórek M … +3 more , Dropko P, Wojtal K, Rejdak K
Prion · 2018 Mar · PMID 29380664 · Full text
We reported the case of a patient with Wernicke-Korsakoff syndrome (WKs) as an early clinical manifestation of sporadic Creutzfeld-Jakob disease (sCJD). The 66-year-old female complained of dizziness and imbalance which...
We reported the case of a patient with Wernicke-Korsakoff syndrome (WKs) as an early clinical manifestation of sporadic Creutzfeld-Jakob disease (sCJD). The 66-year-old female complained of dizziness and imbalance which mostly occurred while walking. A neurological examination revealed a triad of symptoms characteristic for WKs such as gaze paresis, ataxia of limbs and trunk as well as memory disturbances with confabulations. The disturbances increased during the course of the disease, which led to the death of the patient four months after the appearance of the signs. The patient was finally diagnosed with sCJD disease. The most useful ancillary examination results supporting sCJD diagnosis were brain diffusion DWI MRI (diffusion weighted magnetic resonance imaging) and the presence of 14-3-3 protein in CSF (cerebrospinal fluid). Since that manifestation of sCJD is very unique other causes should be taken into consideration while making a final diagnosis.
Differential effects of divalent cations on elk prion protein fibril formation and stability.
Samorodnitsky D, Nicholson EM
Prion · 2018 Jan · PMID 29310497 · Full text
Misfolding of the normally folded prion protein of mammals (PrP) into infectious fibrils causes a variety of diseases, from scrapie in sheep to chronic wasting disease (CWD) in cervids. The misfolded form of PrP, termed...
Misfolding of the normally folded prion protein of mammals (PrP) into infectious fibrils causes a variety of diseases, from scrapie in sheep to chronic wasting disease (CWD) in cervids. The misfolded form of PrP, termed PrP, or in this case PrP, interacts with PrP to create more PrP. This process is not clearly defined but is affected by the presence and interactions of biotic and abiotic cofactors. These include nucleic acids, lipids, glycosylation, pH, and ionic character. PrP has been shown to act as a copper-binding protein in vivo, though it also binds to other divalents as well. The significance of this action has not been conclusively elucidated. Previous reports have shown that metal binding sites occur throughout the N-terminal region of PrP. Other cations like manganese have also been shown to affect PrP abundance in a transcript-independent fashion. Here, we examined the ability of different divalent cations to influence the stability and in vitro conversion of two variants of PrP from elk (L/M132, 26-234). We find that copper and zinc de-stabilize PrP. We also find that PrP M132 exhibits a greater degree of divalent cation induced destabilization than L132. This supports findings that leucine at position 132 confers resistance to CWD, while M132 is susceptible. However, in vitro conversion of PrP is equally suppressed by either copper or zinc, in both L132 and M132 backgrounds. This report demonstrates the complex importance of ionic character on the PrP folding pathway selection on the route to PrP formation.
The role of the prion protein in the internalization of α-synuclein amyloids.
De Cecco E, Legname G
Prion · 2018 Jan · PMID 29308725 · Full text
Synucleinopathies are a group of neurodegenerative diseases characterized by the accumulation of α-synuclein amyloids in several regions of the brain. α-Synuclein fibrils are able to spread via cell-to-cell transfer, and...
Synucleinopathies are a group of neurodegenerative diseases characterized by the accumulation of α-synuclein amyloids in several regions of the brain. α-Synuclein fibrils are able to spread via cell-to-cell transfer, and once inside the cells, they can template the misfolding and aggregation of the endogenous α-synuclein. Multiple mechanisms have been shown to participate in the process of propagation: endocytosis, tunneling nanotubes and macropinocytosis. Recently, we published a research showing that the cellular form of the prion protein (PrP) acts as a receptor for α-synuclein amyloid fibrils, facilitating their internalization through and endocytic pathway. This interaction occurs by a direct interaction between the fibrils and the N-terminal domain of PrP. In cell lines expressing the pathological form of PrP (PrP), the binding between PrP and α-synuclein fibrils prevents the formation and accumulation of PrP, since PrP is no longer available as a substrate for the pathological conversion templated by PrP. On the contrary, PrP deposits are cleared over passages, probably due to the increased processing of PrP into the neuroprotective fragments N1 and C1. Starting from these data, in this work we present new insights into the role of PrP in the internalization of protein amyloids and the possible therapeutic applications of these findings.
Overexpression of a conserved HSP40 chaperone reduces toxicity of several neurodegenerative disease proteins.
Park SK, Arslan F, Kanneganti V … +4 more , Barmada SJ, Purushothaman P, Verma SC, Liebman SW
Prion · 2018 Jan · PMID 29308690 · Full text
TDP-43 and FUS are DNA/RNA binding proteins associated with neuronal inclusions in amyotrophic lateral sclerosis (ALS) patients. Other neurodegenerative diseases are also characterized by neuronal protein aggregates, e.g...
TDP-43 and FUS are DNA/RNA binding proteins associated with neuronal inclusions in amyotrophic lateral sclerosis (ALS) patients. Other neurodegenerative diseases are also characterized by neuronal protein aggregates, e.g. Huntington's disease, associated with polyglutamine (polyQ) expansions in the protein huntingtin. Here we discuss our recent paper establishing similarities between aggregates of TDP-43 that have short glutamine and asparagine (Q/N)-rich modules and are soluble in detergents, with those of polyQ and PIN4C that have large Q/N-rich domains and are detergent-insoluble. We also present new, similar data for FUS. Together, we show that like overexpression of polyQ or PIN4C, overexpression of FUS or TDP-43 causes inhibition of the ubiquitin proteasome system (UPS) and toxicity, both of which are mitigated by overexpression of the Hsp40 chaperone Sis1. Also, in all cases toxicity is enhanced by the [PIN] prion. In addition, we show that the Sis1 mammalian homolog DNAJBI reduces toxicity arising from overexpressed FUS and TDP-43 respectively in human embryonic kidney cells and primary rodent neurons. The common properties of these proteins suggest that heterologous aggregates may enhance the toxicity of a variety of disease-related aggregating proteins, and further that chaperones and the UPS may be key therapeutic targets for diseases characterized by protein inclusions.
Pathological progression of genetic Creutzfeldt-Jakob disease with a PrP V180I mutation.
Akagi A, Iwasaki Y, Mimuro M … +3 more , Kitamoto T, Yamada M, Yoshida M
Prion · 2018 Jan · PMID 29264994 · Full text
In comparison to sporadic Creutzfeldt-Jakob disease (sCJD) with MM1-type and MM2- cortical (MM2C)-type, genetic CJD with a prion protein gene V180I mutation (V180I gCJD) is clinically characterized by onset at an older a...
In comparison to sporadic Creutzfeldt-Jakob disease (sCJD) with MM1-type and MM2- cortical (MM2C)-type, genetic CJD with a prion protein gene V180I mutation (V180I gCJD) is clinically characterized by onset at an older age, slower progress, and the absence of visual disturbances or cerebellar symptoms. In terms of pathological characteristics, gliosis and neuronal loss are generally milder in degree, and characteristic spongiform change can be observed at both the early and advanced stages. However, little is known on the progress of spongiform change over time or its mechanisms. In this study, to elucidate the pathological course of V180I gCJD, statistical analysis of the size and dispersion of the major diameters of vacuoles in six V180I gCJD cases was performed, with five MM1-type sCJD and MM2C-type sCJD cases as controls. As a result, V180I gCJD showed no significant difference in vacuolar diameter regardless of disease duration. In addition, the dispersion of the major diameters of vacuoles in V180I gCJD was larger than that in the MM1-type, which was smaller than that in the MM2C-type. We speculated that the absence of difference in the size of the vacuoles regardless of disease duration suggests that tissue rarefaction does not result from the expansion of vacuole size and increase in number of vacuoles in V180Ig CJD. These features were considered to be significant pathological findings of V180I gCJD.
Curing of [PSI] by Hsp104 Overexpression: Clues to solving the puzzle.
Greene LE, Zhao X, Eisenberg E
Prion · 2018 Jan · PMID 29227184 · Full text
The yeast [PSI] prion, which is the amyloid form of Sup35, has the unusual property of being cured not only by the inactivation of, but also by the overexpression of Hsp104. Even though this latter observation was made m...
The yeast [PSI] prion, which is the amyloid form of Sup35, has the unusual property of being cured not only by the inactivation of, but also by the overexpression of Hsp104. Even though this latter observation was made more than two decades ago, the mechanism of curing by Hsp104 overexpression has remained controversial. This question has been investigated in depth by our laboratory by combining live cell imaging of GFP-labeled Sup35 with standard plating assays of yeast overexpressing Hsp104. We will discuss why the curing of [PSI] by Hsp104 overexpression is not compatible with a mechanism of either inhibition of severing of the prion seeds or asymmetric segregation of the seeds. Instead, our recent data (J. Biol. Chem. 292:8630-8641) indicate that curing is due to dissolution of the prion seeds, which in turn is dependent on the trimming activity of Hsp104. This trimming activity decreases the size of the seeds by dissociating monomers from the fibers, but unlike Hsp104 severing activity, it does not increase the number of prion seeds. Finally, we will discuss the other factors that affect the curing of [PSI] by Hsp104 overexpression and how these factors may relate to the trimming activity of Hsp104.
Neuronal pathophysiology featuring PrP and its control over Ca metabolism.
Bertoli A, Sorgato MC
Prion · 2018 Jan · PMID 29227178 · Full text
Calcium (Ca) is an intracellular second messenger that ubiquitously masters remarkably diverse biological processes, including cell death. Growing evidence substantiates an involvement of the prion protein (PrP) in regul...
Calcium (Ca) is an intracellular second messenger that ubiquitously masters remarkably diverse biological processes, including cell death. Growing evidence substantiates an involvement of the prion protein (PrP) in regulating neuronal Ca homeostasis, which could rationalize most of the wide range of functions ascribed to the protein. We have recently demonstrated that PrP controls extracellular Ca fluxes, and mitochondrial Ca uptake, in neurons stimulated with glutamate (De Mario et al., J Cell Sci 2017; 130:2736-46), suggesting that PrP protects neurons from threatening Ca overloads and excitotoxicity. In light of these results and of recent reports in the literature, here we review the connection of PrP with Ca metabolism and also provide some speculative hints on the physiologic outcomes of this link. In addition, because PrP is implicated in neurodegenerative diseases, including prion disorders and Alzheimer's disease, we will also discuss possible ways by which disruption of PrP-Ca association could be mechanistically connected with these pathologies.
The associations of two SNPs in miRNA-146a and one SNP in ZBTB38-RASA2 with the disease susceptibility and the clinical features of the Chinese patients of sCJD and FFI.
Gao C, Shi Q, Wei J … +5 more , Zhou W, Xiao K, Wang J, Shi Q, Dong XP
Prion · 2018 Jan · PMID 29216791 · Full text
Prion diseases are a group of fatal neurodegenerative disorders that affect humans and animals. Besides of the pathological agent, prion, there are some elements that can influence or determine susceptibility to prion in...
Prion diseases are a group of fatal neurodegenerative disorders that affect humans and animals. Besides of the pathological agent, prion, there are some elements that can influence or determine susceptibility to prion infection and the clinical phenotype of the diseases, e.g., the polymorphism in PRNP gene. Another polymorphism in ZBTB38-RASA2 has been observed to be associated with the susceptibility of sporadic Creutzfeldt-Jacob disease (sCJD) in UK. MicroRNAs are endogenous small noncoding RNAs that control gene expression by targeting mRNAs and triggering either translation repression or RNA degradation. In this study, two polymorphic loci in miR-146a (rs2910164 and rs57095329) and one locus in ZBTB38-RASA2 (rs295301) of 561 Chinese patients of sCJD and 31 cases of fatal familial insomnia (FFI) were screened by PCR and sequencing. Our data did not figure out any association of those three SNPs with the susceptibility of sCJD. However, a significant association of the SNP of rs57095329 in miR-146a showed the association with the susceptibility of FFI. Additionally, the SNP of rs57095329 showed statistical significances with the appearances of mutism and the positive of cerebrospinal fluid (CSF) protein 14-3-3 in sCJD patients, while the SNP of ZBTB38-RASA2 was significantly related with the appearance of myoclonus in sCJD patients. It indicates that the SNPs of ZBTB38-RASA2 and miR-146a are not associated with the susceptibility of the Chinese sCJD patients, but may influence the appearances of clinical manifestations somehow.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe