scholarly journals The sheddase ADAM10 is a potent modulator of prion disease

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Hermann C Altmeppen ◽  
Johannes Prox ◽  
Susanne Krasemann ◽  
Berta Puig ◽  
Katharina Kruszewski ◽  
...  
Keyword(s):  
Nervous System ◽  
Prion Disease ◽  
Prion Diseases ◽  
Spatiotemporal Analysis ◽  
Proteolytic Processing ◽  
Conditional Knockout ◽  
Morphological Data ◽  
Prion Infection ◽  
The Impact

The prion protein (PrPC) is highly expressed in the nervous system and critically involved in prion diseases where it misfolds into pathogenic PrPSc. Moreover, it has been suggested as a receptor mediating neurotoxicity in common neurodegenerative proteinopathies such as Alzheimer's disease. PrPC is shed at the plasma membrane by the metalloprotease ADAM10, yet the impact of this on prion disease remains enigmatic. Employing conditional knockout mice, we show that depletion of ADAM10 in forebrain neurons leads to posttranslational increase of PrPC levels. Upon prion infection of these mice, clinical, biochemical, and morphological data reveal that lack of ADAM10 significantly reduces incubation times and increases PrPSc formation. In contrast, spatiotemporal analysis indicates that absence of shedding impairs spread of prion pathology. Our data support a dual role for ADAM10-mediated shedding and highlight the role of proteolytic processing in prion disease.

The Neuroimmune Interface in Prion Diseases

Physiology ◽  
2000 ◽  
Vol 15 (5) ◽  
pp. 250-255
Author(s):  
Michael A. Klein ◽  
Adriano Aguzzi
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Immune System ◽  
Prion Disease ◽  
Neurodegenerative Disorders ◽  
Prion Diseases ◽  
The Central Nervous System

Prion diseases are fatal neurodegenerative disorders of animals and humans. Here we address the role of the immune system in the spread of prions from peripheral sites to the central nervous system and its potential relevance to iatrogenic prion disease.

scholarly journals Extraneural Prion Neuroinvasion without Lymphoreticular System Infection

2005 ◽  
Vol 79 (18) ◽  
pp. 11858-11863 ◽  
Author(s):  
Jason C. Bartz ◽  
Crista DeJoia ◽  
Tammy Tucker ◽  
Anthony E. Kincaid ◽  
Richard A. Bessen
Keyword(s):  
Lymph Nodes ◽  
Prion Disease ◽  
Prion Diseases ◽  
Cranial Nerves ◽  
Clinical Disease ◽  
Spongiform Encephalopathy ◽  
Peripheral Tissues ◽  
Prion Infection ◽  
Spleen And Lymph Nodes

ABSTRACT While prion infection of the lymphoreticular system (LRS) is necessary for neuroinvasion in many prion diseases, in bovine spongiform encephalopathy and atypical cases of sheep scrapie there is evidence to challenge that LRS infection is required for neuroinvasion. Here we investigated the role of prion infection of LRS tissues in neuroinvasion following extraneural inoculation with the HY and DY strains of the transmissible mink encephalopathy (TME) agent. DY TME agent infectivity was not detected in spleen or lymph nodes following intraperitoneal inoculation and clinical disease was not observed following inoculation into the peritoneum or lymph nodes, or after oral ingestion. In contrast, inoculation of the HY TME agent by each of these peripheral routes resulted in replication in the spleen and lymph nodes and induced clinical disease. To clarify the role of the LRS in neuroinvasion, the HY and DY TME agents were also inoculated into the tongue because it is densely innervated and lesions on the tongue, which are common in ruminants, increase the susceptibility of hamsters to experimental prion disease. Following intratongue inoculation, the DY TME agent caused prion disease and was detected in both the tongue and brainstem nuclei that innervate the tongue, but the prion protein PrPSc was not detected in the spleen or lymph nodes. These findings indicate that the DY TME agent can spread from the tongue to the brain along cranial nerves and neuroinvasion does not require agent replication in the LRS. These studies provide support for prion neuroinvasion from highly innervated peripheral tissues in the absence of LRS infection in natural prion diseases of livestock.

scholarly journals Distribution of microRNA profiles in pre-clinical and clinical forms of murine and human prion disease

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Lesley Cheng ◽  
Camelia Quek ◽  
Xia Li ◽  
Shayne A. Bellingham ◽  
Laura J. Ellett ◽  
...  
Keyword(s):  
Prion Disease ◽  
Molecular Subtype ◽  
Prion Diseases ◽  
Clinical Stage ◽  
Clinical Samples ◽  
Serum Samples ◽  
Prion Infection ◽  
Clinical Forms ◽  
Therapeutic Development ◽  
The Brain

AbstractPrion diseases are distinguished by long pre-clinical incubation periods during which prions actively propagate in the brain and cause neurodegeneration. In the pre-clinical stage, we hypothesize that upon prion infection, transcriptional changes occur that can lead to early neurodegeneration. A longitudinal analysis of miRNAs in pre-clinical and clinical forms of murine prion disease demonstrated dynamic expression changes during disease progression in the affected thalamus region and serum. Serum samples at each timepoint were collected whereby extracellular vesicles (EVs) were isolated and used to identify blood-based biomarkers reflective of pathology in the brain. Differentially expressed EV miRNAs were validated in human clinical samples from patients with human sporadic Creutzfeldt-Jakob disease (sCJD), with the molecular subtype at codon 129 either methionine-methionine (MM, n = 14) or valine-valine (VV, n = 12) compared to controls (n = 20). EV miRNA biomarkers associated with prion infection predicted sCJD with an AUC of 0.800 (85% sensitivity and 66.7% specificity) in a second independent validation cohort (n = 26) of sCJD and control patients with MM or VV subtype. This study discovered clinically relevant miRNAs that benefit diagnostic development to detect prion-related diseases and therapeutic development to inhibit prion infectivity.

scholarly journals The Role of Mcl-1 in Embryonic Neural Precursor Cell Apoptosis

2021 ◽  
Vol 9 ◽  
Author(s):  
Robert T. Flemmer ◽  
Sarah P. Connolly ◽  
Brittany A. Geizer ◽  
Joseph T. Opferman ◽  
Jacqueline L. Vanderluit
Keyword(s):  
Spinal Cord ◽  
Nervous System ◽  
Precursor Cell ◽  
Embryonic Lethality ◽  
Conditional Knockout ◽  
Neural Precursor ◽  
Null Mouse ◽  
Neural Precursor Cell ◽  
Thoracic Spinal Cord

Myeloid cell leukemia-1 (Mcl-1), an anti-apoptotic Bcl-2 protein, regulates neural precursor cell (NPC) survival in both the developing and adult mammalian nervous system. It is unclear when during the neurogenic period Mcl-1 becomes necessary for NPC survival and whether Bax is the sole pro-apoptotic target of Mcl-1. To address these questions, we used the nervous system-specific Nestin-Cre Mcl-1 conditional knockout mouse line (Mcl-1 CKO) to assess the anti-apoptotic role of Mcl-1 in developmental neurogenesis. Loss of Mcl-1 resulted in a wave of apoptosis beginning in the brainstem and cervical spinal cord at embryonic day 9.5 (E9.5) and in the forebrain at E10.5. Apoptosis was first observed ventrally in each region and spread dorsally over time. Within the spinal cord, apoptosis also spread in a rostral to caudal direction following the path of differentiation. Breeding the Mcl-1 CKO mouse with the Bax null mouse rescued the majority of NPC from apoptosis except in the dorsomedial brainstem and ventral thoracic spinal cord where only 50% were rescued. This demonstrates that Mcl-1 promotes NPC survival primarily by inhibiting the activation of Bax, but that Bax is not the sole pro-apoptotic target of Mcl-1 during embryonic neurogenesis. Interestingly, although co-deletion of Bax rescued the majority of NPC apoptosis, it resulted in embryonic lethality at E13, whereas conditional deletion of both Mcl-1 and Bax rescued embryonic lethality. In summary, this study demonstrates the widespread dependency on Mcl-1 during nervous system development.

scholarly journals Role and Therapeutic Potential of Melatonin in the Central Nervous System and Cancers

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1567
Author(s):  
Sangiliyandi Gurunathan ◽  
Min-Hee Kang ◽  
Jin-Hoi Kim
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Circadian Rhythms ◽  
Pineal Gland ◽  
Therapeutic Potential ◽  
Neurological Diseases ◽  
Dark Phase ◽  
Anti Inflammatory ◽  
The Impact

Melatonin (MLT) is a powerful chronobiotic hormone that controls a multitude of circadian rhythms at several levels and, in recent times, has garnered considerable attention both from academia and industry. In several studies, MLT has been discussed as a potent neuroprotectant, anti-apoptotic, anti-inflammatory, and antioxidative agent with no serious undesired side effects. These characteristics raise hopes that it could be used in humans for central nervous system (CNS)-related disorders. MLT is mainly secreted in the mammalian pineal gland during the dark phase, and it is associated with circadian rhythms. However, the production of MLT is not only restricted to the pineal gland; it also occurs in the retina, Harderian glands, gut, ovary, testes, bone marrow, and lens. Although most studies are limited to investigating the role of MLT in the CNS and related disorders, we explored a considerable amount of the existing literature. The objectives of this comprehensive review were to evaluate the impact of MLT on the CNS from the published literature, specifically to address the biological functions and potential mechanism of action of MLT in the CNS. We document the effectiveness of MLT in various animal models of brain injury and its curative effects in humans. Furthermore, this review discusses the synthesis, biology, function, and role of MLT in brain damage, and as a neuroprotective, antioxidative, anti-inflammatory, and anticancer agent through a collection of experimental evidence. Finally, it focuses on the effect of MLT on several neurological diseases, particularly CNS-related injuries.

scholarly journals Pathogenic Prion Protein Isoforms Are Not Present in Cerebral Organoids Generated from Asymptomatic Donors Carrying the E200K Mutation Associated with Familial Prion Disease

Pathogens ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 482
Author(s):  
Simote Foliaki ◽  
Bradley Groveman ◽  
Jue Yuan ◽  
Ryan Walters ◽  
Shulin Zhang ◽  
...  
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Neurological Disorders ◽  
Prion Diseases ◽  
Three Dimensional ◽  
Protein Isoforms ◽  
Genetic Modifiers ◽  
Neuronal Tissue ◽  
Prion Infection ◽  
E200k Mutation

Cerebral organoids (COs) are a self-organizing three-dimensional brain tissue mimicking the human cerebral cortex. COs are a promising new system for modelling pathological features of neurological disorders, including prion diseases. COs expressing normal prion protein (PrPC) are susceptible to prion infection when exposed to the disease isoforms of PrP (PrPD). This causes the COs to develop aspects of prion disease pathology considered hallmarks of disease, including the production of detergent-insoluble, protease-resistant misfolded PrPD species capable of seeding the production of more misfolded species. To determine whether COs can model aspects of familial prion diseases, we produced COs from donor fibroblasts carrying the E200K mutation, the most common cause of human familial prion disease. The mature E200K COs were assessed for the hallmarks of prion disease. We found that up to 12 months post-differentiation, E200K COs harbored no PrPD as confirmed by the absence of detergent-insoluble, protease-resistant, and seeding-active PrP species. Our results suggest that the presence of the E200K mutation within the prion gene is insufficient to cause disease in neuronal tissue. Therefore, other factors, such as further genetic modifiers or aging processes, may influence the onset of misfolding.

scholarly journals Neuroinflammation as Fuel for Axonal Regeneration in the Injured Vertebrate Central Nervous System

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Ilse Bollaerts ◽  
Jessie Van houcke ◽  
Lien Andries ◽  
Lies De Groef ◽  
Lieve Moons
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Axonal Regeneration ◽  
Current Knowledge ◽  
Cord Injury ◽  
The Central Nervous System ◽  
Novel Therapeutic Strategies ◽  
The Impact ◽  
Vertebrate Central Nervous System

Damage to the central nervous system (CNS) is one of the leading causes of morbidity and mortality in elderly, as repair after lesions or neurodegenerative disease usually fails because of the limited capacity of CNS regeneration. The causes underlying this limited regenerative potential are multifactorial, but one critical aspect is neuroinflammation. Although classically considered as harmful, it is now becoming increasingly clear that inflammation can also promote regeneration, if the appropriate context is provided. Here, we review the current knowledge on how acute inflammation is intertwined with axonal regeneration, an important component of CNS repair. After optic nerve or spinal cord injury, inflammatory stimulation and/or modification greatly improve the regenerative outcome in rodents. Moreover, the hypothesis of a beneficial role of inflammation is further supported by evidence from adult zebrafish, which possess the remarkable capability to repair CNS lesions and even restore functionality. Lastly, we shed light on the impact of aging processes on the regenerative capacity in the CNS of mammals and zebrafish. As aging not only affects the CNS, but also the immune system, the regeneration potential is expected to further decline in aged individuals, an element that should definitely be considered in the search for novel therapeutic strategies.

scholarly journals Prion propagation in mice lacking central nervous system NF-κB signalling

2008 ◽  
Vol 89 (6) ◽  
pp. 1545-1550 ◽  
Author(s):  
C. Julius ◽  
M. Heikenwalder ◽  
P. Schwarz ◽  
A. Marcel ◽  
M. Karin ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Immune Responses ◽  
Published Data ◽  
Histopathological Changes ◽  
Prion Infection ◽  
Prion Propagation ◽  
Proliferation Regulation ◽  
The Impact ◽  
The Brain

Prions induce highly typical histopathological changes including cell death, spongiosis and activation of glia, yet the molecular pathways leading to neurodegeneration remain elusive. Following prion infection, enhanced nuclear factor-κB (NF-κB) activity in the brain parallels the first pathological changes. The NF-κB pathway is essential for proliferation, regulation of apoptosis and immune responses involving induction of inflammation. The IκB kinase (IKK) signalosome is crucial for NF-κB signalling, consisting of the catalytic IKKα/IKKβ subunits and the regulatory IKKγ subunit. This study investigated the impact of NF-κB signalling on prion disease in mouse models with a central nervous system (CNS)-restricted elimination of IKKβ or IKKγ in nearly all neuroectodermal cells, including neurons, astrocytes and oligodendrocytes, and in mice containing a non-phosphorylatable IKKα subunit (IKKα AA/AA). In contrast to previously published data, the observed results showed no evidence supporting the hypothesis that impaired NF-κB signalling in the CNS impacts on prion pathogenesis.

scholarly journals Diagnosis of prion diseases by RT-QuIC results in improved surveillance

Neurology ◽  
2020 ◽  
Vol 95 (8) ◽  
pp. e1017-e1026 ◽  
Author(s):  
Daniel D. Rhoads ◽  
Aleksandra Wrona ◽  
Aaron Foutz ◽  
Janis Blevins ◽  
Kathleen Glisic ◽  
...  
Keyword(s):  
Sensitivity And Specificity ◽  
Prion Disease ◽  
Disease Surveillance ◽  
Prion Diseases ◽  
False Negative ◽  
High Sensitivity ◽  
Disease Type ◽  
Diagnostic Sensitivity ◽  
Class Iii ◽  
The Impact

ObjectiveTo present the National Prion Disease Pathology Surveillance Center's (NPDPSC’s) experience using CSF real-time quaking-induced conversion (RT-QuIC) as a diagnostic test, to examine factors associated with false-negative RT-QuIC results, and to investigate the impact of RT-QuICs on prion disease surveillance.MethodsBetween May 2015 and April 2018, the NPDPSC received 10,498 CSF specimens that were included in the study. Sensitivity and specificity analyses were performed on 567 autopsy-verified cases. Prion disease type, demographic characteristics, specimen color, and time variables were examined for association with RT-QuIC results. The effect of including positive RT-QuIC cases in prion disease surveillance was examined.ResultsThe diagnostic sensitivity and specificity of RT-QuIC across all prion diseases were 90.3% and 98.5%, respectively. Diagnostic sensitivity was lower for fatal familial insomnia, Gerstmann-Sträussler-Scheinker disease, sporadic fatal insomnia, variably protease sensitive prionopathy, and the VV1 and MM2 subtypes of sporadic Creutzfeldt-Jakob disease. Individuals with prion disease and negative RT-QuIC results were younger and had lower tau levels and nonelevated 14-3-3 levels compared to RT-QuIC–positive cases. Sensitivity was high throughout the disease course. Some cases that initially tested RT-QuIC negative had a subsequent specimen test positive. Including positive RT-QuIC cases in surveillance statistics increased laboratory-based case ascertainment of prion disease by 90% over autopsy alone.ConclusionsRT-QuIC has high sensitivity and specificity for diagnosing prion diseases. Sensitivity limitations are associated with prion disease type, age, and related CSF diagnostic results. RT-QuIC greatly improves laboratory-based prion disease ascertainment for surveillance purposes.Classification of evidenceThis study provides Class III evidence that second-generation RT-QuIC identifies prion disease with a sensitivity of 90.3% and specificity of 98.5% among patients being screened for these diseases due to concerning symptoms.

scholarly journals Role of Long Non-Coding RNAs in Conferring Resistance in Tumors of the Nervous System

2021 ◽  
Vol 11 ◽  
Author(s):  
Soudeh Ghafouri-Fard ◽  
Amin Agabalazadeh ◽  
Atefe Abak ◽  
Hamed Shoorei ◽  
Mohammad Mehdi Hassanzadeh Taheri ◽  
...  
Keyword(s):  
Nervous System ◽  
High Mortality ◽  
Chemotherapeutic Agents ◽  
Morbidity Rate ◽  
Mortality And Morbidity ◽  
Non Coding Rnas ◽  
The Impact ◽  
Emergence Of Resistance

Tumors of the nervous system can be originated from several locations. They mostly have high mortality and morbidity rate. The emergence of resistance to chemotherapeutic agents is a hurdle in the treatment of patients. Long non-coding RNAs (lncRNAs) have been shown to influence the response of glioblastoma/glioma and neuroblastoma to chemotherapeutic agents. MALAT1, NEAT1, and H19 are among lncRNAs that affect the response of glioma/glioblastoma to chemotherapy. As well as that, NORAD, SNHG7, and SNHG16 have been shown to be involved in conferring this phenotype in neuroblastoma. Prior identification of expression amounts of certain lncRNAs would help in the better design of therapeutic regimens. In the current manuscript, we summarize the impact of lncRNAs on chemoresistance in glioma/glioblastoma and neuroblastoma.

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