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Prion protein misfolding at the synapse

Prion protein misfolding at the synapse
Prion protein misfolding at the synapse

The synapse has emerged as a major target for the misfolding insults that underlie prion disease and many other proteinopathies (e.g., Alzheimer's disease (AD)). This common theme in the pathogenesis of these disorders indicates that analogous degenerative processes could be at play when increasing extracellular and/or intracellular accumulation of misfolded proteins leads to eventual cell loss. Similar therapeutic strategies may thus be effective in various central nervous system amyloidoses. Animal models of prion disease provide good evidence for specific synaptic degeneration within defined anatomical pathways of the hippocampus. Biochemical, histological, and electron microscopy studies have documented disintegrating synaptic structures during the early asymptomatic stage of disease, which has lead to the hypothesis that degenerative pathways are engaged locally at the synapse during an early key stage of neurodegeneration. Mirroring this, synapse loss precedes neuronal loss in early AD, and is more closely correlated with cognitive impairment than are plaques and tangles. As in other protein misfolding neurodegenerative disorders, it is likely that in prion disease, pathological prion protein conformers are present and actively participate in disease pathogenesis at the synapse. Despite this fundamental understanding, there has been little systematic study of the evidence for pathological accumulation of prion protein in either the presynaptic or postsynaptic specializations, or indeed the role of cellular pathways and synaptic proteins associated with these pathologies. This chapter will review key signaling pathways and processes implicated in biochemical changes that misfolded prion protein triggers at the synapse. Knowing what these changes are may well lead to new drug targets that would then enable us to prevent neuronal cell loss.

289-312
Springer New York, NY
Šišková, Zuzana
517d75b4-f152-4232-9e0a-2bc600ac022f
Perry, V. Hugh
8f29d36a-8e1f-4082-8700-09483bbaeae4
Asuni, Ayodeji A.
b1412b1b-9794-4705-aada-aed5d3da038f
Wyttenbach, Andreas
O'Connor, Vincent
Šišková, Zuzana
517d75b4-f152-4232-9e0a-2bc600ac022f
Perry, V. Hugh
8f29d36a-8e1f-4082-8700-09483bbaeae4
Asuni, Ayodeji A.
b1412b1b-9794-4705-aada-aed5d3da038f
Wyttenbach, Andreas
O'Connor, Vincent

Šišková, Zuzana, Perry, V. Hugh and Asuni, Ayodeji A. (2010) Prion protein misfolding at the synapse. In, Wyttenbach, Andreas and O'Connor, Vincent (eds.) Folding for the Synapse. Springer New York, NY, pp. 289-312. (doi:10.1007/978-1-4419-7061-9_15).

Record type: Book Section

Abstract

The synapse has emerged as a major target for the misfolding insults that underlie prion disease and many other proteinopathies (e.g., Alzheimer's disease (AD)). This common theme in the pathogenesis of these disorders indicates that analogous degenerative processes could be at play when increasing extracellular and/or intracellular accumulation of misfolded proteins leads to eventual cell loss. Similar therapeutic strategies may thus be effective in various central nervous system amyloidoses. Animal models of prion disease provide good evidence for specific synaptic degeneration within defined anatomical pathways of the hippocampus. Biochemical, histological, and electron microscopy studies have documented disintegrating synaptic structures during the early asymptomatic stage of disease, which has lead to the hypothesis that degenerative pathways are engaged locally at the synapse during an early key stage of neurodegeneration. Mirroring this, synapse loss precedes neuronal loss in early AD, and is more closely correlated with cognitive impairment than are plaques and tangles. As in other protein misfolding neurodegenerative disorders, it is likely that in prion disease, pathological prion protein conformers are present and actively participate in disease pathogenesis at the synapse. Despite this fundamental understanding, there has been little systematic study of the evidence for pathological accumulation of prion protein in either the presynaptic or postsynaptic specializations, or indeed the role of cellular pathways and synaptic proteins associated with these pathologies. This chapter will review key signaling pathways and processes implicated in biochemical changes that misfolded prion protein triggers at the synapse. Knowing what these changes are may well lead to new drug targets that would then enable us to prevent neuronal cell loss.

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Published date: 22 October 2010

Identifiers

Local EPrints ID: 489351
URI: http://eprints.soton.ac.uk/id/eprint/489351
PURE UUID: ecb8fab7-b266-4812-9cd0-5e3b566ff85b

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Date deposited: 22 Apr 2024 16:38
Last modified: 05 Jun 2024 19:09

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Contributors

Author: Zuzana Šišková
Author: V. Hugh Perry
Author: Ayodeji A. Asuni
Editor: Andreas Wyttenbach
Editor: Vincent O'Connor

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