Synaptic degeneration is the primary neuropathological feature in prion disease

Clinton, J.; Forsyth, C.S.; Royston, M.C.; Roberts, Gareth W.

doi:10.1097/00001756-199301000-00017

Cited by 95 publications

(57 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…For example, synaptic changes correlate with early behavioral signs and precede neuronal degeneration in several models of murine scrapie (29,30). In addition, synaptic disorganization and loss have been described in sporadic and inherited Creutzfeldt-Jakob disease, including cases associated with octapeptide insertions (31). Accumulation of abnormal PrP at presynaptic and postsynaptic sites has been found to precede neuronal dysfunction and death and be associated with loss of synaptic contacts in the CNS of scrapie-infected mice and patients with CreutzfeldtJakob disease (29,(32)(33)(34).…”

Section: Synaptic Dysfunction In Prion and Other Neurodegenerative DImentioning

confidence: 99%

Baxdeletion prevents neuronal loss but not neurological symptoms in a transgenic model of inherited prion disease

Chiesa

Piccardo

Dossena

et al. 2004

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

View full text Add to dashboard Cite

Transgenic Tg(PG14) mice express a mutant prion protein containing 14 octapeptide repeats, whose human homologue is associated with an inherited prion dementia. These mice develop a progressive neurological disorder characterized by ataxia and cerebellar atrophy, with massive apoptotic degeneration of granule neurons. Bax, a proapoptotic gene of the Bcl-2 family, plays a key role in regulating cell death in the nervous system. To analyze the role of Bax in the Tg(PG14) phenotype, we crossed Tg(PG14) mice with Bax ؊/؊ mice to obtain Tg(PG14)͞Bax ؊/؊ offspring. Bax deletion effectively rescued cerebellar granule neurons from apoptosis, implying that these cells die via a Bax-dependent process. Surprisingly, however, the age at which symptoms began and the duration of the clinical phase of the illness were not altered in Tg(PG14)͞ Bax ؊/؊ mice. In addition, Bax deletion failed to prevent shrinkage of the molecular layer of the cerebellum and loss of synaptophysinpositive synaptic endings. Our analysis indicates that synaptic loss makes a critical contribution to the Tg(PG14) phenotype. These results provide insights into the pathogenesis of prion diseases and have important implications for the treatment of these disorders.synapse ͉ apoptosis ͉ neurodegeneration ͉ cerebellum

show abstract

Section: Synaptic Dysfunction In Prion and Other Neurodegenerative DImentioning

confidence: 99%

Baxdeletion prevents neuronal loss but not neurological symptoms in a transgenic model of inherited prion disease

Chiesa

Piccardo

Dossena

et al. 2004

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

View full text Add to dashboard Cite

show abstract

“…Thus, PrP may be important for sleep regulation, because the thalamus is implicated in the regulation of sleep spindles and EEG slow waves (Steriade et al, 1993). PrP is a glycoprotein localized on neuronal membranes and in astrocytes (Collinge et al, 1994;Moser et al, 1995) that may promote neuronal cell differentiation and maintain neuronal function (Clinton et al, 1993), but its function is not yet understood (Estibeiro, 1996). There are indications that the loss of the natural PrP function may be responsible for the pathology in prion diseases .…”

mentioning

confidence: 99%

Sleep and Sleep Regulation in Normal and Prion Protein-Deficient Mice

Tobler¹,

Deboer²,

1997

View full text Add to dashboard Cite

Mice are the preferred mammalian species for genetic investigations of the role of proteins. The normal function of the prion protein (PrP) is unknown, although it plays a major role in the prion diseases, including fatal familial insomnia. We investigated its role in sleep and sleep regulation by comparing baseline recordings and the effects of sleep deprivation in PrP knockout mice (129/SV) and wild-type controls (129/SV ϫ C57BL/6), which are the mice used for most gene targeting experiments and whose behavior is not well characterized. Although no difference was evident in the amount of vigilance states, the null mice exhibited a larger degree of sleep fragmentation than the wild-type with almost double the amount of short waking episodes. As in other rodents, cortical temperature closely reflected the time course of waking. The increase of slow-wave activity (SWA; mean EEG power density in the 0.25-4.0 Hz range) at waking to nonrapid eye movement (NREM) sleep transitions was faster and reached a lower level in the null mice than in the wild-type. The contribution of the lower frequencies (0.25-5.0 Hz) to the spectrum was smaller than in other rodents in all three vigilance states, and the distinction between NREM sleep and REM sleep was most marked in the theta band. After the sleep deprivation, SWA was increased, but the changes in EEG power density and SWA were more prominent and lasted longer in the PrP-null mice. Our results suggest that PrP plays a role in promoting sleep continuity.

show abstract

“…75, -2545Neurochem. 75, (2000.The prion-related encephalopathies, including scrapie and bovine spongiform encephalopathy in livestock and Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome, and kuru in humans, are neurodegenerative disorders characterized by early synaptic loss, astrocytosis, progressive neuronal loss, and often cerebral protein aggregation and deposition (Gajdusek et al, 1966;Clinton et al, 1993;Fraser, 1993;Jeffrey et al, 1994). These diseases appear to be caused by the posttranslational and conformational transition of the normal cellular prion protein (PrP) isoform, PrP C , into the abnormal and pathogenic PrP isoform, PrP SC (Prusiner, 1982(Prusiner, , 1991Hope and Manson, 1991).…”

mentioning

confidence: 99%

The Role of Prion Peptide Structure and Aggregation in Toxicity and Membrane Binding

Rymer

Good

2000

Journal of Neurochemistry

View full text Add to dashboard Cite

Prion diseases are neurodegenerative disorders associated with a conformational change in the normal cellular isoform of the prion protein, PrP C , to an abnormal scrapie isoform, PrP SC . Unlike the ␣-helical PrP C , the protease-resistant core of PrP SC is predominantly ␤-sheet and possesses a tendency to polymerize into amyloid fibrils. We performed experiments with two synthetic human prion peptides, and , to determine how peptide structure affects neurotoxicity and protein-membrane interactions. Peptide solutions possessing ␤-sheet and amyloid structures were neurotoxic to PC12 cells in vitro and bound with measurable affinities to cholesterol-rich phospholipid membranes at ambient conditions, but peptide solutions lacking stable ␤-sheet structures and amyloid content were nontoxic and possessed less than one tenth of the binding affinities of the amyloid-containing peptides. Regardless of structure, the peptide binding affinities to cholesterol-depleted membranes were greatly reduced. These results suggest that the ␤-sheet and amyloid structures of the prion peptides give rise to their toxicity and membrane binding affinities and that membrane binding affinity, especially in cholesterol-rich environments, may be related to toxicity. Our results may have significance in understanding the role of the fibrillogenic cerebral deposits associated with some of the prion diseases in neurodegeneration and may have implications for other amyloidoses. Key Words: Circular dichroismSpongiform encephalopathies-Cell membranes. J. Neurochem. 75, 2536Neurochem. 75, -2545Neurochem. 75, (2000.The prion-related encephalopathies, including scrapie and bovine spongiform encephalopathy in livestock and Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome, and kuru in humans, are neurodegenerative disorders characterized by early synaptic loss, astrocytosis, progressive neuronal loss, and often cerebral protein aggregation and deposition (Gajdusek et al., 1966;Clinton et al., 1993;Fraser, 1993;Jeffrey et al., 1994). These diseases appear to be caused by the posttranslational and conformational transition of the normal cellular prion protein (PrP) isoform, PrP C , into the abnormal and pathogenic PrP isoform, PrP SC (Prusiner, 1982(Prusiner, , 1991Hope and Manson, 1991). Fourier transform infrared spectroscopy and circular dichroism (CD) demonstrate that PrP C is predominantly ␣-helical (42%) with little ␤-sheet structure (3%). However, the protease-resistant core of PrP SC is mostly ␤-sheet (43%) with less ␣-helical structure (30%), and it has a tendency to polymerize into amyloid fibrils (Prusiner et al., 1983;Pan et al., 1993;Safar et al., 1993;Baldwin et al., 1994). Based on these structural measurements, researchers have postulated that PrP SC formation involves a conformational transformation resulting in increased ␤-sheet content (Pan et al., 1993;Safar et al., 1993;Baldwin et al., 1994).Structural changes similar to the PrP C to PrP SC conformational conversion associated with prion diseases ar...

show abstract

Synaptic degeneration is the primary neuropathological feature in prion disease

Cited by 95 publications

References 0 publications

Baxdeletion prevents neuronal loss but not neurological symptoms in a transgenic model of inherited prion disease

Baxdeletion prevents neuronal loss but not neurological symptoms in a transgenic model of inherited prion disease

Sleep and Sleep Regulation in Normal and Prion Protein-Deficient Mice

The Role of Prion Peptide Structure and Aggregation in Toxicity and Membrane Binding

Contact Info

Product

Resources

About