Proteomics Analysis of Amyloid and Nonamyloid Prion Disease Phenotypes Reveals Both Common and Divergent Mechanisms of Neuropathogenesis

Moore, Roger A.; Sturdevant, Dan E.; Chesebro, Bruce; Priola, Suzette A.

doi:10.1021/pr500329w

Cited by 21 publications

(28 citation statements)

References 84 publications

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“…These data show that dysregulation of mitochondrial ETC proteins at clinical stages of prion disease accompany severe bioenergetics deficits in 263K-infected Tg7 mice which may contribute to organismal death. Our results are consistent with other studies that have reported altered mitochondrial protein and mRNA levels in both prion-infected mice and human CJD subjects (28,29).…”

Section: Discussionsupporting

confidence: 93%

“…Other studies have reported dysregulation of superoxide dismutase (SOD) enzymes or oxidative stress during prion disease (26,29,37), and we hypothesized that changes in the oxidation status of ETC proteins would be observed in Tg7 Sc mice, leading us to perform a PTM analysis of Tg7 Sc and Tg7 NBH mice. However, we did not detect any significant differences in oxidized methionines or other PTMs indicative of oxidation damage to ETC proteins.…”

Section: Discussionmentioning

confidence: 99%

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Mitochondrial Respiration Is Impaired during Late-Stage Hamster Prion Infection

Faris

Moore

Ward

et al. 2017

J Virol

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Mitochondria are crucial to proper neuronal function and overall brain health. Mitochondrial dysfunction within the brain has been observed in many neurodegenerative diseases, including prion disease. Several markers of decreased mitochondrial activity during prion infection have been reported, yet the bioenergetic respiratory status of mitochondria from prion-infected animals is unknown. Here we show that clinically ill transgenic mice overexpressing hamster prion protein (Tg7) infected with the hamster prion strain 263K suffer from a severe deficit in mitochondrial oxygen consumption in response to the respiratory complex II substrate succinate. Characterization of the mitochondrial proteome of purified brain mitochondria from infected and uninfected Tg7 mice showed significant differences in the relative abundance of key mitochondrial electron transport proteins in 263K-infected animals relative to that in controls. Our results suggest that at clinical stages of prion infection, dysregulation of respiratory chain proteins may lead to impairment of mitochondrial respiration in the brain. Mitochondrial dysfunction is present in most major neurodegenerative diseases, and some studies have suggested that mitochondrial processes may be altered during prion disease. Here we show that hamster prion-infected transgenic mice overexpressing the hamster prion protein (Tg7 mice) suffer from mitochondrial respiratory deficits. Tg7 mice infected with the 263K hamster prion strain have little or no signs of mitochondrial dysfunction at the disease midpoint but suffer from a severe deficit in mitochondrial respiration at the clinical phase of disease. A proteomic analysis of the isolated brain mitochondria from clinically affected animals showed that several proteins involved in electron transport, mitochondrial dynamics, and mitochondrial protein synthesis were dysregulated. These results suggest that mitochondrial dysfunction, possibly exacerbated by prion protein overexpression, occurs at late stages during 263K prion disease and that this dysfunction may be the result of dysregulation of mitochondrial proteins.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Mitochondrial Respiration Is Impaired during Late-Stage Hamster Prion Infection

Faris

Moore

Ward

et al. 2017

J Virol

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“…To determine whether PrP C localization to the mitochondrion was dependent on PrP C overexpression or age, we utilized 6–12 week old wild-type C57BL/6 mice as well as transgenic mice that overexpress PrP C (RM and Tg3F4). We also used 6–12 week old Tg44 transgenic mice which underexpress GPI-anchorless PrP C 35 36 to determine whether the GPI anchor was necessary for mitochondrial localization. Mitochondria were isolated from fresh brain tissue of C57BL/6, RM, Tg3F4, and Tg44 mice using the MACS isolation procedure as described in methods.…”

Section: Resultsmentioning

confidence: 99%

Cellular prion protein is present in mitochondria of healthy mice

Faris

Moore

Race

et al. 2017

Sci Rep

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Cellular prion protein (PrPC) is a mammalian glycoprotein which is usually found anchored to the plasma membrane via a glycophosphatidylinositol (GPI) anchor. PrPC misfolds to a pathogenic isoform PrPSc, the causative agent of neurodegenerative prion diseases. The precise function of PrPC remains elusive but may depend upon its cellular localization. Here we show that PrPC is present in brain mitochondria from 6–12 week old wild-type and transgenic mice in the absence of disease. Mitochondrial PrPC was fully processed with mature N-linked glycans and did not require the GPI anchor for localization. Protease treatment of purified mitochondria suggested that mitochondrial PrPC exists as a transmembrane isoform with the C-terminus facing the mitochondrial matrix and the N-terminus facing the intermembrane space. Taken together, our data suggest that PrPC can be found in mitochondria in the absence of disease, old age, mutation, or overexpression and that PrPC may affect mitochondrial function.

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“…Consistently, disruption in the expression of proteins involved in Ca 2+ homoeostasis and synaptic vesicle transport were also found in Tg44 mice with CAA (Ref. 178). …”

Section: Role Of Apoptosis In Tsesmentioning

confidence: 53%

Mechanisms of prion-induced neurodegeneration

Saá

Červen̆áková

2016

Expert Rev. Mol. Med.

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Transmissible spongiform encephalopathies (TSEs), or prion diseases, are fatal neurodegenerative disorders characterised by long incubation period, short clinical duration, and transmissibility to susceptible species. Neuronal loss, spongiform changes, gliosis and the accumulation in the brain of the misfolded version of a membrane-bound cellular prion protein (PrP C ), termed PrP TSE , are diagnostic markers of these diseases. Compelling evidence links protein misfolding and its accumulation with neurodegenerative changes. Accordingly, several mechanisms of prion-mediated neurotoxicity have been proposed. In this paper, we provide an overview of the recent knowledge on the mechanisms of neuropathogenesis, the neurotoxic PrP species and the possible therapeutic approaches to treat these devastating disorders.

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Proteomics Analysis of Amyloid and Nonamyloid Prion Disease Phenotypes Reveals Both Common and Divergent Mechanisms of Neuropathogenesis

Cited by 21 publications

References 84 publications

Mitochondrial Respiration Is Impaired during Late-Stage Hamster Prion Infection

Mitochondrial Respiration Is Impaired during Late-Stage Hamster Prion Infection

Cellular prion protein is present in mitochondria of healthy mice

Mechanisms of prion-induced neurodegeneration

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