scholarly journals Prion Strain Targeting Independent of Strain-Specific Neuronal Tropism

2008 ◽  
Vol 83 (1) ◽  
pp. 81-87 ◽  
Author(s):  
Jacob I. Ayers ◽  
Anthony E. Kincaid ◽  
Jason C. Bartz
Keyword(s):  
Differential Susceptibility ◽  
Underlying Mechanism ◽  
Clinical Disease ◽  
Prion Strain ◽  
Deposition Patterns ◽  
Prion Infection ◽  
The Central Nervous System ◽  
Motor Tracts ◽  
Spongiform Degeneration ◽  
Transmissible Mink Encephalopathy

ABSTRACT While neuropathological features that define prion strains include spongiform degeneration and deposition patterns of PrPSc, the underlying mechanism for the strain-specific differences in PrPSc targeting is not known. To investigate prion strain targeting, we inoculated hamsters in the sciatic nerve with either the hyper (HY) or drowsy (DY) strain of the transmissible mink encephalopathy (TME) agent. Both TME strains were initially retrogradely transported in the central nervous system (CNS) exclusively by four descending motor tracts. The locations of HY and DY PrPSc deposition were identical throughout the majority of the incubation period. However, differences in PrPSc deposition between these strains were observed upon development of clinical disease. The differences observed were unlikely to be due to strain-specific neuronal tropism, since comparison of PrPSc deposition patterns by different routes of infection indicated that all brain areas were susceptible to prion infection by both TME strains. These findings suggest that prion transport and differential susceptibility to prion infection are not solely responsible for prion strain targeting. The data suggest that differences in PrPSc distribution between strains during clinical disease are due to differences in the length of time that PrPSc has to spread in the CNS before the host succumbs to disease.

scholarly journals Coinfecting Prion Strains Compete for a Limiting Cellular Resource

2010 ◽  
Vol 84 (11) ◽  
pp. 5706-5714 ◽  
Author(s):  
Ronald A. Shikiya ◽  
Jacob I. Ayers ◽  
Charles R. Schutt ◽  
Anthony E. Kincaid ◽  
Jason C. Bartz
Keyword(s):  
Protein Misfolding ◽  
Neuronal Loss ◽  
Infectious Agent ◽  
Prion Strain ◽  
Prion Strains ◽  
The Central Nervous System ◽  
Transmissible Mink Encephalopathy ◽  
Prion Conversion ◽  
Cellular Components

ABSTRACT Prion strain interference can influence the emergence of a dominant strain from a mixture; however, the mechanisms underlying prion strain interference are poorly understood. In our model of strain interference, inoculation of the sciatic nerve with the drowsy (DY) strain of the transmissible mink encephalopathy (TME) agent prior to superinfection with the hyper (HY) strain of TME can completely block HY TME from causing disease. We show here that the deposition of PrPSc, in the absence of neuronal loss or spongiform change, in the central nervous system corresponds with the ability of DY TME to block HY TME infection. This suggests that DY TME agent-induced damage is not responsible for strain interference but rather prions compete for a cellular resource. We show that protein misfolding cyclic amplification (PMCA) of DY and HY TME maintains the strain-specific properties of PrPSc and replicates infectious agent and that DY TME can interfere, or completely block, the emergence of HY TME. DY PrPSc does not convert all of the available PrPC to PrPSc in PMCA, suggesting the mechanism of prion strain interference is due to the sequestering of PrPC and/or other cellular components required for prion conversion. The emergence of HY TME in PMCA was controlled by the initial ratio of the TME agents. A higher ratio of DY to HY TME agent is required for complete blockage of HY TME in PMCA compared to several previous in vivo studies, suggesting that HY TME persists in animals coinfected with the two strains. This was confirmed by PMCA detection of HY PrPSc in animals where DY TME had completely blocked HY TME from causing disease.

scholarly journals Microglia Are Critical in Host Defense against Prion Disease

2018 ◽  
Vol 92 (15) ◽  
Author(s):  
James A. Carroll ◽  
Brent Race ◽  
Katie Williams ◽  
James Striebel ◽  
Bruce Chesebro
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Prion Disease ◽  
Host Defense ◽  
Clinical Signs ◽  
Clinical Disease ◽  
Oral Drug ◽  
Early Event ◽  
Prion Infection ◽  
The Central Nervous System

ABSTRACT Microglial cells in the central nervous system play important roles in neurodevelopment and resistance to infection, yet microglia can become neurotoxic under some conditions. An early event during prion infection is the activation of microglia and astrocytes in the brain prior to damage or death of neurons. Previous prion disease studies using two different strategies to manipulate signaling through the microglial receptor CSF-1R reported contrary effects on survival from prion disease. However, in these studies, reductions of microglial numbers and function were variable, thus confounding interpretation of the results. In the present work, we used oral treatment with a potent inhibitor of CSF-1R, PLX5622, to eliminate 78 to 90% of microglia from cortex early during the course of prion infection. Oral drug treatment early after infection with the RML scrapie strain significantly accelerated vacuolation, astrogliosis, and deposition of disease-associated prion protein. Furthermore, drug-treated mice had advanced clinical disease requiring euthanasia 31 days earlier than untreated control mice. Similarly, PLX5622 treatment during the preclinical phase at 80 days postinfection with RML scrapie also accelerated disease and resulted in euthanasia of mice 33 days earlier than infected controls. PLX5622 also accelerated clinical disease after infection with scrapie strains ME7 and 22L. Thus, microglia are critical in host defense during prion disease. The early accumulation of PrPSc in the absence of microglia suggested that microglia may function by clearing PrPSc, resulting in longer survival. IMPORTANCE Microglia contribute to many aspects of health and disease. When activated, microglia can be beneficial by repairing damage in the central nervous system (CNS) or they can turn harmful by becoming neurotoxic. In prion and prionlike diseases, the involvement of microglia in disease is unclear. Previous studies suggest that microglia can either speed up or slow down disease. In this study, we infected mice with prions and depleted microglia from the brains of mice using PLX5622, an effective CSF-1R tyrosine kinase inhibitor. Microglia were markedly reduced in brains, and prion disease was accelerated, so that mice needed to be euthanized 20 to 33 days earlier than infected control mice due to advanced clinical disease. Similar results occurred when mice were treated with PLX5622 at 80 days after infection, which was just prior to the start of clinical signs. Thus, microglia are important for removing prions, and the disease is faster when microglia are depleted.

scholarly journals Tick populations from endemic and non-endemic areas in Germany show differential susceptibility to TBEV

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Katrin Liebig ◽  
Mathias Boelke ◽  
Domenic Grund ◽  
Sabine Schicht ◽  
Andrea Springer ◽  
...  
Keyword(s):  
Differential Susceptibility ◽  
Feeding Rates ◽  
Infection Rates ◽  
Lower Saxony ◽  
Tick Borne Encephalitis ◽  
The Central Nervous System ◽  
Tick Borne Encephalitis Virus ◽  
In Vitro Feeding ◽  
Tbev Infection

Abstract Tick-borne encephalitis virus (TBEV) is endemic in twenty-seven European countries, transmitted via the bite of an infected tick. TBEV is the causative agent of one of the most important viral diseases of the central nervous system (CNS). In Germany, 890 human cases were registered between the years 2018–2019. The castor bean tick, Ixodes ricinus, is the TBEV vector with the highest importance in Central Europe, including Germany. Despite the nationwide distribution of this tick species, risk areas of TBEV are largely located in Southern Germany. To increase our understanding of TBEV-tick interactions, we collected ticks from different areas within Germany (Haselmühl/Bavaria, Hanover/Lower Saxony) and infected them via an in vitro feeding system. A TBEV isolate was obtained from an endemic focus in Haselmühl. In two experimental series conducted in 2018 and 2019, ticks sampled in Haselmühl (TBEV focus) showed higher artificial feeding rates, as well as higher TBEV infections rates than ticks from the non-endemic area (Hanover). Other than the tick origin, year and month of the infection experiment as well as co-infection with Borrelia spp., had a significant impact on TBEV Haselmühl infection rates. Taken together, these findings suggest that a specific adaptation of the tick populations to their respective TBEV virus isolates or vice versa, leads to higher TBEV infection rates in those ticks. Furthermore, co-infection with other tick-borne pathogens such as Borrelia spp. can lower TBEV infection rates in specific populations.

scholarly journals Metformin Treatment Inhibits Motility and Invasion of Glioblastoma Cancer Cells

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Marwa Al Hassan ◽  
Isabelle Fakhoury ◽  
Zeinab El Masri ◽  
Noura Ghazale ◽  
Rayane Dennaoui ◽  
...  
Keyword(s):  
Cell Motility ◽  
Cancer Cells ◽  
Anticancer Agents ◽  
Underlying Mechanism ◽  
Cellular Adhesion ◽  
Response To Treatment ◽  
Metformin Treatment ◽  
The Central Nervous System ◽  
Treatment Of Diabetes ◽  
U87 Cells

Glioblastoma multiforme (GBM) is one of the most common and deadliest cancers of the central nervous system (CNS). GBMs high ability to infiltrate healthy brain tissues makes it difficult to remove surgically and account for its fatal outcomes. To improve the chances of survival, it is critical to screen for GBM-targeted anticancer agents with anti-invasive and antimigratory potential. Metformin, a commonly used drug for the treatment of diabetes, has recently emerged as a promising anticancer molecule. This prompted us, to investigate the anticancer potential of metformin against GBMs, specifically its effects on cell motility and invasion. The results show a significant decrease in the survival of SF268 cancer cells in response to treatment with metformin. Furthermore, metformin’s efficiency in inhibiting 2D cell motility and cell invasion in addition to increasing cellular adhesion was also demonstrated in SF268 and U87 cells. Finally, AKT inactivation by downregulation of the phosphorylation level upon metformin treatment was also evidenced. In conclusion, this study provides insights into the anti-invasive antimetastatic potential of metformin as well as its underlying mechanism of action.

Spongiform neurodegenerative disease in a Persian kitten

2007 ◽  
Vol 9 (3) ◽  
pp. 242-245 ◽  
Author(s):  
Claudia Salvadori ◽  
Laura Lossi ◽  
Mario Arispici ◽  
Carlo Cantile
Keyword(s):  
Cerebral Cortex ◽  
Neurodegenerative Disease ◽  
Head Tilt ◽  
Vestibular Nuclei ◽  
Vacuolar Degeneration ◽  
History Of ◽  
The Central Nervous System ◽  
Spongiform Degeneration ◽  
Old Persian ◽  
Phosphorylated Neurofilaments

A congenital encephalopathy with spongiform degeneration and prominent neuronal apoptosis was observed in a 4-month-old Persian male cat with a history of depressed mental status and ataxia. On clinical examination, signs included right head tilt, ventroflexion of the head and neck, and tetraparesis. Histological examination of the central nervous system revealed multifocal, bilateral and symmetrical vacuolar degeneration of the neuropil, mainly involving the cerebellar and vestibular nuclei area, the caudal colliculi, the mesencephalic nuclei, the tegmental area and the deeper layer of the cerebral cortex. Accumulation of phosphorylated neurofilaments was detected in neuronal perikarya of the deep cortical layers, hippocampus and thalamus. Numerous pyknotic and apoptotic neurons were also observed in the cerebral cortex. These neuropathological changes differ from those observed in previous reports of spongiform degeneration of the grey matter in cats and were suggestive of a congenital neurodegenerative disease.

scholarly journals Loss of PIKfyve drives the spongiform degeneration in prion diseases

2021 ◽  
Author(s):  
Asvin KK Lakkaraju ◽  
Karl Frontzek ◽  
Emina Lemes ◽  
Uli Herrmann ◽  
Marco Losa ◽  
...  
Keyword(s):  
Cultured Cells ◽  
Prion Diseases ◽  
Brain Slices ◽  
Prion Infection ◽  
Unfolded Protein ◽  
Phosphatidylinositol Kinase ◽  
Jakob Disease ◽  
Infected Cells ◽  
Spongiform Degeneration ◽  
Protein Response

Brain-matter vacuolation is a defining trait of all prion diseases, yet its cause is unknown. Here we report that prion infection and prion-mimetic antibodies deplete the phosphatidylinositol kinase PIKfyve in mouse brains, cultured cells, organotypic brain slices, and in brains of Creutzfeldt-Jakob Disease victims. We found that PIKfyve, an inositol kinase involved endolysosomal maturation, is acylated by zDHHC9 and zDHHC21, whose juxtavesicular topology is disturbed by prion infection, resulting in PIKfyve deacylation and destabilization. A protracted unfolded protein response (UPR), typical of prion diseases, also induced PIKfyve deacylation and degradation. Conversely, UPR antagonists restored PIKfyve levels in prion-infected cells. Overexpression of zDHHC9 and zDHHC21, administration of the antiprion polythiophene LIN5044, or supplementation with the PIKfyve reaction product PI(3,5)P2, suppressed prion-induced vacuolation. Thus, PIKfyve emerges as a central mediator of vacuolation and neurotoxicity in prion diseases.

scholarly journals Cannabinoid WIN 55,212-2 Inhibits Human Glioma Cell Growth by Triggering ROS-Mediated Signal Pathways

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Kun Wang ◽  
Qian Wang ◽  
Qinghao Li ◽  
Zhaoqiang Zhang ◽  
Jing Gao ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Dna Damage ◽  
Ex Vivo ◽  
Underlying Mechanism ◽  
Migration And Invasion ◽  
Signal Pathways ◽  
Human Glioma ◽  
U251 Cell ◽  
The Central Nervous System

Glioblastoma is a highly invasive primary malignant tumor of the central nervous system. Cannabinoid analogue WIN 55,212-2 (WIN) exhibited a novel anticancer effect against human tumors. However, the anticancer potential and underlying mechanism of WIN against human glioma remain unclear. Herein, the anticancer efficiency and mechanism of WIN in U251 human glioma cells were investigated. The results showed that WIN dose-dependently inhibited U251 cell proliferation, migration, and invasion in vitro. WIN treatment also effectively suppressed U251 tumor spheroids growth ex vivo. Further studies found that WIN induced significant apoptosis as convinced by the caspase-3 activation and release of cytochrome C. Mechanism investigation revealed that WIN triggered ROS-mediated DNA damage and caused dysfunction of VEGF-AKT/FAK signal axis. However, ROS inhibition effectively attenuated WIN-induced DNA damage and dysfunction of VEGF-AKT/FAK signal axis and eventually improved U251 cell proliferation, migration, and invasion. Taken together, our findings validated that WIN had the potential to inhibit U251 cell proliferation, migration, and invasion and induce apoptosis by triggering ROS-dependent DNA damage and dysfunction of VEGF-AKT/FAK signal axis.

On the Alterations of the Central Nervous System in the Acute Confusional Psychoses [Nuovo Contributo alla Conoscenza delle Alterazioni del Sistema nervoso centrale nelle Psicosi acute confusionali]. (Riv. di Patol., Nerv. e Ment., fasc. 8, 1901.) Cauria, M.

1902 ◽  
Vol 48 (200) ◽  
pp. 184-185
Author(s):  
J. R. Gilmour
Keyword(s):  
Central Nervous System ◽  
Nerve Cell ◽  
Upper Limbs ◽  
Secondary Degeneration ◽  
The Third ◽  
Pyramidal Tracts ◽  
Axis Cylinder ◽  
The Central Nervous System ◽  
Motor Tracts ◽  
Tendon Reflexes

This is the third paper by this author on the same subject. In this case the types of alteration of the nerve-cells were two:—First, the disintegration of the chromatic substance which, reduced to fine granules, was scattered uniformly through the cell, rendering it homogeneous; the nucleus central and unaltered. This is the usual type following toxines. Second, the type with central chromatolysis and deformity, and displacement of the nucleus. This is the type following the cutting of the axis-cylinder process. In this case, this was associated with degeneration of the fibres of various parts of the motor tracts, and was probably an example of the secondary degeneration of the nerve-cell from “reaction at a distance.” The lesion in the pyramidal tracts of the cord stands in relation to the symptoms presented by the patient, e. g. hypertonus, exaggeration of the tendon reflexes, paresis of the upper limbs. The curability of such cases is not in contradiction with the anatomical facts, as the alteration in the nerve-cell is reparable. The primary degeneration of the fibres is probably due to the same toxine as had produced the nerve-cell change.

Cerebrocortical Degeneration in Goats Inoculated with Mink-passaged Scrapie Virus

1986 ◽  
Vol 23 (5) ◽  
pp. 543-549 ◽  
Author(s):  
W. J. Hadlow ◽  
R. E. Race
Keyword(s):  
Cortical Lesion ◽  
Common Occurrence ◽  
Intracerebral Inoculation ◽  
Sheep Brain ◽  
Spongiform Degeneration ◽  
The Common ◽  
Transmissible Mink Encephalopathy ◽  
The One ◽  
Ranch Mink ◽  
Topographic Pattern

Widespread spongiform degeneration of the cerebral cortex occurred in four African pygmy goats that became affected with scrapie after intracerebral inoculation with scrapie virus (Suffolk sheep brain origin) that had been passed three times in ranch mink. The occurrence of such cerebrocortical degeneration was a distinct departure from the topographic pattern of neuropathologic changes that characterizes scrapie in sheep and goats. But the cortical lesion was identical to the one found in goats that became affected with a disease otherwise indistinguishable from scrapie after intracerebral inoculation with transmissible mink encephalopathy (TME) virus that had been passed twice in mink. If TME originated from infection with wild scrapie virus, as is generally thought, then the viruses used in these two instances would be equivalent in their passage history in this aberrant host. Given this similarity, the common occurrence of the cortical lesion is thought to be consistent with the view that TME virus almost certainly is scrapie virus whose biologic properties became altered by chance passage in ranch mink.

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