Altered trafficking of abnormal prion protein in atypical scrapie: prion protein accumulation in oligodendroglial inner mesaxons

Jeffrey, Martin; González, Lorenzo; Simmons, Marion; Hunter, Nora; Martin, Stuart; McGovern, Gillian

doi:10.1111/nan.12302

Cited by 7 publications

(5 citation statements)

References 44 publications

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“…In agreement with previous findings in tg338 with AS [51,53,70], all AS isolates produced intense vacuolar and micro-vacuolar degeneration, mainly located in the superior colliculus, thalamus, hippocampus, septum and cerebral cortices, as shown by lesion profile (Fig 1A). Micro-vacuolation was also observed in the white matter, substantia nigra and caudate putamen.…”

Section: Strain Identity Between Norwegian and Italian As Isolatessupporting

confidence: 92%

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A single amino acid residue in bank vole prion protein drives permissiveness to Nor98/atypical scrapie and the emergence of multiple strain variants

et al. 2022

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Prions are infectious agents that replicate through the autocatalytic misfolding of the cellular prion protein (PrPC) into infectious aggregates (PrPSc) causing fatal neurodegenerative diseases in humans and animals. Prions exist as strains, which are encoded by conformational variants of PrPSc. The transmissibility of prions depends on the PrPC sequence of the recipient host and on the incoming prion strain, so that some animal prion strains are more contagious than others or are transmissible to new species, including humans. Nor98/atypical scrapie (AS) is a prion disease of sheep and goats reported in several countries worldwide. At variance with classical scrapie (CS), AS is considered poorly contagious and is supposed to be spontaneous in origin. The zoonotic potential of AS, its strain variability and the relationships with the more contagious CS strains remain largely unknown. We characterized AS isolates from sheep and goats by transmission in ovinised transgenic mice (tg338) and in two genetic lines of bank voles, carrying either methionine (BvM) or isoleucine (BvI) at PrP residue 109. All AS isolates induced the same pathological phenotype in tg338 mice, thus proving that they encoded the same strain, irrespective of their geographical origin or source species. In bank voles, we found that the M109I polymorphism dictates the susceptibility to AS. BvI were susceptible and faithfully reproduced the AS strain, while the transmission in BvM was highly inefficient and was characterized by a conformational change towards a CS-like prion strain. Sub-passaging experiments revealed that the main strain component of AS is accompanied by minor CS-like strain components, which can be positively selected during replication in both AS-resistant or AS-susceptible animals. These findings add new clues for a better comprehension of strain selection dynamics in prion infections and have wider implications for understanding the origin of contagious prion strains, such as CS.

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Section: Strain Identity Between Norwegian and Italian As Isolatessupporting

confidence: 92%

“…Intracellular PrP Sc deposition was not observed. Remarkably, the pathological phenotype observed in BvI matches that described in small ruminant AS, with the main involvement of rostral areas, distinctive immunolabeling in white matter and lack of intracellular PrP Sc deposition [ 34 , 70 , 71 ].…”

Section: Resultsmentioning

confidence: 79%

A single amino acid residue in bank vole prion protein drives permissiveness to Nor98/atypical scrapie and the emergence of multiple strain variants

et al. 2022

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“…The PrP-3F4 staining we observed is consistent with previous work associating dense, rounded PrP C staining with dystrophic axonal processes in non-prion neurodegenerative diseases [25], atypical scrapie [37], and areas of ischemic brain damage [26]. Thus, it was possible that PrP-3F4 was localizing to axons in our IC inoculated mice.…”

Section: Resultssupporting

confidence: 91%

Altered distribution, aggregation, and protease resistance of cellular prion protein following intracranial inoculation

et al. 2019

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Prion protein (PrP C ) is a protease-sensitive and soluble cell surface glycoprotein expressed in almost all mammalian cell types. PrP Sc , a protease-resistant and insoluble form of PrP C , is the causative agent of prion diseases, fatal and transmissible neurogenerative diseases of mammals. Prion infection is initiated via either ingestion or inoculation of PrP Sc or when host PrP C stochastically refolds into PrP Sc . In either instance, the early events that occur during prion infection remain poorly understood. We have used transgenic mice expressing mouse PrP C tagged with a unique antibody epitope to monitor the response of host PrP C to prion inoculation. Following intracranial inoculation of either prion-infected or uninfected brain homogenate, we show that host PrP C can accumulate both intra-axonally and within the myelin membrane of axons suggesting that it may play a role in axonal loss following brain injury. Moreover, in response to the inoculation host PrP C exhibits an increased insolubility and protease resistance similar to that of PrP Sc , even in the absence of infectious prions. Thus, our results raise the possibility that damage to the brain may be one trigger by which PrP C stochastically refolds into pathogenic PrP Sc leading to productive prion infection.

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“…Moreover, PRP SC is localized as arrays adjacent to myelin fibers in the cerebrum and cerebellum in CJD (El Hachimi et al, 1998). This is borne out by the observation of PrP in the inner mesaxon and paranodal cytoplasm of oligodendroglia in atypical (but not in classical) scrapie, thus supporting the idea that certain prion strains may interfere in trafficking between axons and oligodendroglia (Jeffrey et al, 2017). Altered astrocyte/oligodendrocyte interactions are probably important in the pathogenesis of CJD and other glial prionopathies.…”

Section: Creutzfeldt-jakob's Disease (Cjd) and Other Prion Diseasesmentioning

confidence: 78%

Oligodendrogliopathy in neurodegenerative diseases with abnormal protein aggregates: The forgotten partner

Ferrer

2018

Progress in Neurobiology

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Oligodendrocytes are in contact with neurons, wrap axons with a myelin sheath that protects their structural integrity, and facilitate nerve conduction. Oligodendrocytes also form a syncytium with astrocytes which interacts with neurons, promoting reciprocal survival mediated by activity and by molecules involved in energy metabolism and trophism. Therefore, oligodendrocytes are key elements in the normal functioning of the central nervous system. Oligodendrocytes are affected following different insults to the central nervous system including ischemia, traumatism, and inflammation. The term oligodendrogliopathy highlights the prominent role of altered oligodendrocytes in the pathogenesis of certain neurological diseases, not only in demyelinating diseases and most leukodystrophies, but also in aging and age-related neurodegenerative diseases with abnormal protein aggregates. Most of these diseases are characterized by the presence of abnormal protein deposits, forming characteristic and specific inclusions in neurons and astrocytes but also in oligodendrocytes, thus signaling their involvement in the disease. Emerging evidence suggests that such deposits in oligodendrocytes are not mere bystanders but rather are associated with functional alterations. Moreover, operative modifications in oligodendrocytes are also detected in the absence of oligodendroglial inclusions in certain diseases. The present review focuses first on general aspects of oligodendrocytes and precursors, and their development and functions, and then introduces and updates alterations and dysfunction of oligodendrocytes in selected neurodegenerative diseases with abnormal protein aggregates such as multiple system atrophy, Lewy body diseases, tauopathies, Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal lobar degeneration with TDP-43 inclusions (TDP-43 proteinopathies), and Creutzfeldt-Jakob´s disease as a prototypical human prionopathy.

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Altered trafficking of abnormal prion protein in atypical scrapie: prion protein accumulation in oligodendroglial inner mesaxons

Abstract: These data show that atypical scrapie infection directs a change in trafficking of abnormal PrP to axons and oligodendroglia and that the resulting pathology is an interaction between the agent strain and host genotype.

Cited by 7 publications

References 44 publications

A single amino acid residue in bank vole prion protein drives permissiveness to Nor98/atypical scrapie and the emergence of multiple strain variants

A single amino acid residue in bank vole prion protein drives permissiveness to Nor98/atypical scrapie and the emergence of multiple strain variants

Altered distribution, aggregation, and protease resistance of cellular prion protein following intracranial inoculation

Oligodendrogliopathy in neurodegenerative diseases with abnormal protein aggregates: The forgotten partner

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