Quantification of surviving cerebellar granule neurones and abnormal prion protein (PrP<sup>Sc</sup>) deposition in sporadic Creutzfeldt–Jakob disease supports a pathogenic role for small PrP<sup>Sc</sup> deposits common to the various molecular subtypes

Faucheux, Baptiste; Morain, Émilie; Diouron, V.; Brandel, J.-P.; Salomon, Dominique; Sazdovitch, Véronique; Privat, Nicolas; Laplanche, Jean‐Louis; Hauw, Jean‐Jacques; Haı̈k, Stéphane

doi:10.1111/j.1365-2990.2011.01179.x

Cited by 9 publications

(10 citation statements)

References 41 publications

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“…This suggests that PrP Sc is not the primary effector of prion-induced neurodegeneration. Other studies that related PrP deposits and neuronal loss in the brains of patients with sporadic CJD are consistent with the view that various molecular PrP species with distinct toxic properties may be produced in the terminal phase of the disease (15,16).…”

supporting

confidence: 58%

Prion Propagation and Toxicity Occur In Vitro with Two-Phase Kinetics Specific to Strain and Neuronal Type

Hannaoui

Maatouk

Privat

et al. 2013

J Virol

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e Prion diseases, or transmissible spongiform encephalopathies (TSEs), are fatal neurodegenerative disorders that occur in humans and animals. The neuropathological hallmarks of TSEs are spongiosis, glial proliferation, and neuronal loss. The only known specific molecular marker of TSEs is the abnormal isoform (PrP Sc ) of the host-encoded prion protein (PrP C ), which accumulates in the brain of infected subjects and forms infectious prion particles. Although this transmissible agent lacks a specific nucleic acid component, several prion strains have been isolated. Prion strains are characterized by differences in disease outcome, PrP Sc distribution patterns, and brain lesion profiles at the terminal stage of the disease. The molecular factors and cellular mechanisms involved in strain-specific neuronal tropism and toxicity remain largely unknown. Currently, no cellular model exists to facilitate in vitro studies of these processes. A few cultured cell lines that maintain persistent scrapie infections have been developed, but only two of them have shown the cytotoxic effects associated with prion propagation. In this study, we have developed primary neuronal cultures to assess in vitro neuronal tropism and toxicity of different prion strains (scrapie strains 139A, ME7, and 22L). We have tested primary neuronal cultures enriched in cerebellar granular, striatal, or cortical neurons. Our results showed that (i) a strain-specific neuronal tropism operated in vitro; (ii) the cytotoxic effect varied among strains and neuronal cell types; (iii) prion propagation and toxicity occurred in two kinetic phases, a replicative phase followed by a toxic phase; and (iv) neurotoxicity peaked when abnormal PrP accumulation reached a plateau.

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supporting

confidence: 58%

Prion Propagation and Toxicity Occur In Vitro with Two-Phase Kinetics Specific to Strain and Neuronal Type

Hannaoui

Maatouk

Privat

et al. 2013

J Virol

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“…Ataxia and CGN loss are seen in many patients with prion disease (Collinge et al ., 1992; Faucheux et al ., 2011) and in transgenic mice expressing a prion protein insertional mutation (Chiesa et al ., 2000). Muzaimi et al .…”

Section: Discussionmentioning

confidence: 99%

“…In Cockayne syndrome, a human hereditary DNA repair disorder, CGNs degenerate and are reduced in number (Kohji et al ., 1998). CGN loss also occurs in many prion disease cases (Collinge et al ., 1992; Faucheux et al ., 2011) and in transgenic mice expressing a prion protein with insertional mutation (Chiesa et al ., 2000). Many drugs are associated with drug‐induced cerebellar ataxia (van Gaalen et al ., 2014).…”

Section: Introductionmentioning

confidence: 99%

The Immp2l mutation causes age‐dependent degeneration of cerebellar granule neurons prevented by antioxidant treatment

Liu

Lü

2015

Aging Cell

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SummaryReactive oxygen species are implicated in age‐associated neurodegeneration, although direct in vivo evidence is lacking. We recently showed that mice with a mutation in the Inner Mitochondrial Membrane Peptidase 2‐like (Immp2l) gene had elevated levels of mitochondrial superoxide, impaired fertility and age‐associated phenotypes, including kyphosis and ataxia. Here we show that ataxia and cerebellar hypoplasia occur in old mutant mice (> 16 months). Cerebellar granule neurons (CGNs) are significantly underrepresented; Purkinje cells and cells in the molecular layer are not affected. Treating mutant mice with the mitochondria‐targeted antioxidant SkQ1 from 6 weeks to 21 months protected cerebellar granule neurons. Apoptotic granule neurons were observed in mutant mice but not in age‐matched normal control mice or SkQ1‐treated mice. Old mutant mice showed increased serum protein carbonyl content, cerebellar 4‐hydroxynonenal (HNE), and nitrotyrosine modification compared to old normal control mice. SOD2 expression was increased in Purkinje cells but decreased in granule neurons of old mutant mice. Mitochondrial marker protein VDAC1 also was decreased in CGNs of old mutant mice, suggesting decreased mitochondrial number. SkQ1 treatment decreased HNE and nitrotyrosine modification, and restored SOD2 and VDAC1 expression in CGNs of old mutant mice. Neuronal expression of nitric oxide synthase was increased in cerebella of young mutant mice but decreased in old mutant mice. Our work provides evidence for a causal role of oxidative stress in neurodegeneration of Immp2l mutant mice. The Immp2l mutant mouse model could be valuable in elucidating the role of oxidative stress in age‐associated neurodegeneration.

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“…Small, punctate synaptic deposits of PrP Sc correlate with neuronal loss, whereas the larger, focal types of deposits show an inverse correlation with neuronal counts (9). These findings could be related to the generation of oligomers of low molecular weight, present in brains of sporadic Creutzfeldt-Jakob (CJD) disease patients, that control the progression rate of the disease (10).…”

mentioning

confidence: 92%

Disease-associated Mutations in the Prion Protein Impair Laminin-induced Process Outgrowth and Survival

Machado

Beraldo

Santos

et al. 2012

Journal of Biological Chemistry

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Background: In addition to the toxicity mediated by prion protein misfolding, mechanisms associated with its loss-offunction in genetic prion diseases are unknown. Results: Neural cells expressing PrP C mutants associated with prion diseases present impaired laminin-mediated process outgrowth and survival. Conclusion: PrP C mutants show loss-of-function in neural cells. Significance: The impairment of prion protein functions may contribute to the etiology of prion diseases.

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Quantification of surviving cerebellar granule neurones and abnormal prion protein (PrP^Sc) deposition in sporadic Creutzfeldt–Jakob disease supports a pathogenic role for small PrP^Sc deposits common to the various molecular subtypes

Cited by 9 publications

References 41 publications

Prion Propagation and Toxicity Occur In Vitro with Two-Phase Kinetics Specific to Strain and Neuronal Type

Prion Propagation and Toxicity Occur In Vitro with Two-Phase Kinetics Specific to Strain and Neuronal Type

The Immp2l mutation causes age‐dependent degeneration of cerebellar granule neurons prevented by antioxidant treatment

Disease-associated Mutations in the Prion Protein Impair Laminin-induced Process Outgrowth and Survival

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Quantification of surviving cerebellar granule neurones and abnormal prion protein (PrPSc) deposition in sporadic Creutzfeldt–Jakob disease supports a pathogenic role for small PrPSc deposits common to the various molecular subtypes

Cited by 9 publications

References 41 publications

Prion Propagation and Toxicity Occur In Vitro with Two-Phase Kinetics Specific to Strain and Neuronal Type

Prion Propagation and Toxicity Occur In Vitro with Two-Phase Kinetics Specific to Strain and Neuronal Type

The Immp2l mutation causes age‐dependent degeneration of cerebellar granule neurons prevented by antioxidant treatment

Disease-associated Mutations in the Prion Protein Impair Laminin-induced Process Outgrowth and Survival

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Quantification of surviving cerebellar granule neurones and abnormal prion protein (PrP^Sc) deposition in sporadic Creutzfeldt–Jakob disease supports a pathogenic role for small PrP^Sc deposits common to the various molecular subtypes