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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Šišková, Z., Perry, V.H., Asuni, A.A. (2011). Prion Protein Misfolding at the Synapse. In: Wyttenbach, A., O'Connor, V. (eds) Folding for the Synapse. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-7061-9_15
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