Dendritic Pathology in Prion Disease Starts at the Synaptic Spine

Fuhrmann, Martin; Mitteregger, Gerda; Kretzschmar, Hans A.; Herms, Jochen

doi:10.1523/jneurosci.5062-06.2007

Cited by 124 publications

(115 citation statements)

References 52 publications

(76 reference statements)

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“…TPrP-treated PK1 cells underwent neuritic retraction and loss ( Fig. 1 E and H) that have been described as early signs of neuronal damage in prion diseases (31,32) as well as apoptosis (Fig. 3A), a feature of prion pathology (11).…”

Section: Similar Morphological and Molecular Hallmarks Of Tprp-inducedmentioning

confidence: 76%

Highly neurotoxic monomeric α-helical prion protein

Zhou

Ottenberg

Sferrazza

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Prion diseases are infectious and belong to the group of protein misfolding neurodegenerative diseases. In these diseases, neuronal dysfunction and death are caused by the neuronal toxicity of a particular misfolded form of their cognate protein. The ability to specifically target the toxic protein conformer or the neuronal death pathway would provide powerful therapeutic approaches to these diseases. The neurotoxic forms of the prion protein (PrP) have yet to be defined but there is evidence suggesting that at least some of them differ from infectious PrP (PrP Sc ). Herein, without making an assumption about size or conformation, we searched for toxic forms of recombinant PrP after dilution refolding, size fractionation, and systematic biological testing of all fractions. We found that the PrP species most neurotoxic in vitro and in vivo (toxic PrP, TPrP) is a monomeric, highly α-helical form of PrP. TPrP caused autophagy, apoptosis, and a molecular signature remarkably similar to that observed in the brains of prion-infected animals. Interestingly, highly α-helical intermediates have been described for other amyloidogenic proteins but their biological significance remains to be established. We provide unique experimental evidence that a monomeric α-helical form of an amyloidogenic protein represents a cytotoxic species. Although toxic PrP has yet to be purified from prion-infected brains, TPrP might be the equivalent of one highly neurotoxic PrP species generated during prion replication. Because TPrP is a misfolded, highly neurotoxic form of PrP reproducing several features of prion-induced neuronal death, it constitutes a useful model to study PrP-induced neurodegenerative mechanisms.

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Section: Similar Morphological and Molecular Hallmarks Of Tprp-inducedmentioning

confidence: 76%

Highly neurotoxic monomeric α-helical prion protein

Zhou

Ottenberg

Sferrazza

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…In prion diseases, apart from neuronal loss, earliest and potentially most vital neuropathology changes occur at the level of synapses including synapse loss, morphological changes, and functional abnormality (Mallucci, 2009). Two‐photon imaging studies of living, prion‐infected animals found that retraction of dendritic spines occur early during disease progression (Fuhrmann et al ., 2007; Fang et al ., 2016). Changes in their morphology are now believed to underlie synaptic plasticity associated with learning and memory, as well as degenerative events that occur during aging and neurological diseases (Sala & Segal, 2014; Herms & Dorostkar, 2016).…”

Section: Discussionmentioning

confidence: 99%

DLP1‐dependent mitochondrial fragmentation and redistribution mediate prion‐associated mitochondrial dysfunction and neuronal death

Wang

et al. 2017

Aging Cell

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SummaryMitochondrial malfunction is a universal and critical step in the pathogenesis of many neurodegenerative diseases including prion diseases. Dynamin‐like protein 1 (DLP1) is one of the key regulators of mitochondrial fission. In this study, we investigated the role of DLP1 in mitochondrial fragmentation and dysfunction in neurons using in vitro and in vivo prion disease models. Mitochondria became fragmented and redistributed from axons to soma, correlated with increased mitochondrial DLP1 expression in murine primary neurons (N2a cells) treated with the prion peptide PrP106–126 in vitro as well as in prion strain‐infected hamster brain in vivo. Suppression of DLP1 expression by DPL1 RNAi inhibited prion‐induced mitochondrial fragmentation and dysfunction (measured by ADP/ATP ratio, mitochondrial membrane potential, and mitochondrial integrity). We also demonstrated that DLP1 RNAi is neuroprotective against prion peptide in N2a cells as shown by improved cell viability and decreased apoptosis markers, caspase 3 induced by PrP106–126. On the contrary, overexpression of DLP1 exacerbated mitochondrial dysfunction and cell death. Moreover, inhibition of DLP1 expression ameliorated PrP106–126‐induced neurite loss and synaptic abnormalities (i.e., loss of dendritic spine and PSD‐95, a postsynaptic scaffolding protein as a marker of synaptic plasticity) in primary neurons, suggesting that altered DLP1 expression and mitochondrial fragmentation are upstream events that mediate PrP106–126‐induced neuron loss and degeneration. Our findings suggest that DLP1‐dependent mitochondrial fragmentation and redistribution plays a pivotal role in PrPS c‐associated mitochondria dysfunction and neuron apoptosis. Inhibition of DLP1 may be a novel and effective strategy in the prevention and treatment of prion diseases.

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“…dendrites (Fuhrmann et al, 2007) or synapses (Jeffrey et al, 2000), rather than at the soma of neurons. Thus, neuronenriched primary cultures used in the current study will be an invaluable ex vivo model for analysing the mechanism of neurodegeneration caused by prion infection.…”

Section: Discussionmentioning

confidence: 99%

Comparison of abnormal isoform of prion protein in prion-infected cell lines and primary-cultured neurons by PrPSc-specific immunostaining

Tanaka

Fujiwara

Suzuki

et al. 2016

Journal of General Virology

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We established abnormal isoform of prion protein (PrP Sc )-specific double immunostaining using mAb 132, which recognizes aa 119-127 of the PrP molecule, and novel PrP Sc -specific mAb 8D5, which recognizes the N-terminal region of the PrP molecule. Using the PrP Sc -specific double immunostaining, we analysed PrP Sc in immortalized neuronal cell lines and primary cerebralneuronal cultures infected with prions. The PrP Sc -specific double immunostaining showed the existence of PrP Sc positive for both mAbs 132 and 8D5, as well as those positive only for either mAb 132 or mAb 8D5. This indicated that double immunostaining detects a greater number of PrP Sc species than single immunostaining. Double immunostaining revealed cell-type-dependent differences in PrP Sc staining patterns. In the 22 L prion strain-infected Neuro2a (N2a)-3 cells, a subclone of N2a neuroblastoma cell line, or GT1-7, a subclone of the GT1 hypothalamic neuronal cell line, granular PrP Sc stains were observed at the perinuclear regions and cytoplasm, whereas unique string-like PrP Sc stains were predominantly observed on the surface of the 22 L straininfected primary cerebral neurons. Only 14 % of PrP Sc in the 22 L strain-infected N2a-3 cells were positive for mAb 8D5, indicating that most of the PrP Sc in N2a-3 lack the N-terminal portion. In contrast, nearly half PrP Sc detected in the 22 L strain-infected primary cerebral neurons were positive for mAb 8D5, suggesting the abundance of full-length PrP Sc that possesses the Nterminal portion of PrP. Further analysis of prion-infected primary neurons using PrP Sc -specific immunostaining will reveal the neuron-specific mechanism for prion propagation.

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Dendritic Pathology in Prion Disease Starts at the Synaptic Spine

Cited by 124 publications

References 52 publications

Highly neurotoxic monomeric α-helical prion protein

Highly neurotoxic monomeric α-helical prion protein

DLP1‐dependent mitochondrial fragmentation and redistribution mediate prion‐associated mitochondrial dysfunction and neuronal death

Comparison of abnormal isoform of prion protein in prion-infected cell lines and primary-cultured neurons by PrPSc-specific immunostaining

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