NR AXWD
AU Senatore,A.; Colleoni,S.; Restelli,E.; Garofoli,A.; Forloni,G.; Gobbi,M.; Chiesa,R.
TI Presymptomatic Impairment of Glutamate Exocytosis in the Cerebellum of Transgenic Mice Expressing a PrP Insertional Mutation
QU International Conference - Prion 2007 (26.-28.9.2007) Edinburgh International Conference Centre, Edinburgh, Scotland, UK - Book of Abstracts: Pathology and Pathogenesis P03.176
IA http://www.prion2007.com/pdf/Prion Book of Abstracts.pdf
PT Konferenz-Poster
AB
Tg(PG14) mice expressing a mutant prion protein (PrP) associated with an inherited prion disease, accumulate a form of the mutant protein in their brains that is aggregated and weakly protease-resistant. As this form accumulates the mice develop a fatal neurological disorder characterized clinically by ataxia and pathologically by dramatic cerebellar atrophy due to loss of synaptic endings in the molecular layer and apoptosis of granule neurons. In this study we tested the hypothesis that mutant PrP deposition induces early synaptic dysfunction, which precedes neurodegeneration and clinical symptoms. We carried out biochemical analyses of PrP and tested the functional status of glutamatergic and GABAergic neurotransmission in isolated nerve endings (synaptosomes) from Tg(PG14) mice at different stages of neurological illness (between 30 and >400 days of age). Biochemical characterization demonstrated relative enrichment of PrP in cerebellar synaptosomes where the mutant protein was highly aggregated. Glutamatergic synaptosomes from Tg(PG14) cerebellum, but not from cortex, showed impaired depolarization-induced release already in presymptomatic 30 day-old mice. By the time mice had developed clinical disease (> 250 days of age) there was complete impairment of depolarization-induced release. Cerebellar synaptosomes from >150 days old Tg(PG14) mice showed also a significant increase of basal glutamate release. Importantly, there was no impairment of glutamate uptake, excluding non-specific synaptosomal damage as a cause of these findings. No significant differences were found in GABA uptake or exocytotsis.
These results indicate that PG14 PrP deposition is associated with early functional alterations of presynaptic glutamatergic nerve endings in the cerebellum, which degenerate in the later stages of disease. Our analysis supports the hypothesis that aggregation of PrP affects the mechanisms governing neurotransmitter release as an early event in the pathogenesis. Studies are in progress to clarify the specific mechanism by which PG14 PrP leads to defective depolarization-induced glutamate exocytosis.
AD A. Senatore, E. Restelli, A. Garofoli, R. Chiesa, Dulbecco Telethon Institute-Mario Negri Institute, Neuroscience, Italy; S. Colleoni, M. Gobbi, Mario Negri Institute, Biochemistry, Italy; G. Forloni, Mario Negri Institute, Neuroscience, Italy
SP englisch
PO Schottland