NR APGT
AU DeArmond,S.J.; Bouzamondo-Bernstein,E.; Ishikura,N.
TI Synapse Degeneration Precedes Nerve Cell Body Degeneration in the GABAergic System During Scrapie
QU International Conference - Prion diseases: from basic research to intervention concepts - TSE-Forum, 08.10.-10.10.2003, Gasteig, München - Oral sessions OS-21
PT Konferenz-Vortrag
AB For many years we have been testing the hypothesis that formation and accumulation of PrPsc in neurons is the cause of the clinically relevant functional, neurochemical, and morphological abnormalities. Recently, we focused on the GABAergic system of neurons because of the reports that loss of GABAergic neurons is the first neuropathological abnormality in human and animal prion diseases. On the contrary, we were unable to verify selective loss on neocortical GABA immunopositive neurons in the preterminal stages of Sc237 scrapie in Syrian hamsters. Rather, GABA immunogold histochemistry for electronmicroscopy indicated that GABAergic presynaptic boutons degenerate before GABAergic nerve cell bodies; however, the loss of GABAergic boutons occurred at the same rate as non-GABAergic boutons, which further argues against selective vulnerability of this inhibitory system. Two functional abnormalities of GABAergic neurons and presynaptic nerve terminals preceded loss of boutons: (1) GABA was dysfunctionally trafficked out of synaptic regions to the perikaryon of neurons based on unbiased stereological counts, which revealed a 50% increase in the number of GABA immunopositive nerve cell bodies in the neocortex. (2) Evoked 3H-GABA release from GABAergic synaptosomal preparations showed a significant decrease following accumulation of PrPsc in synaptosomal plasma membranes. One ultrastructural abnormality that appears to precede presynaptic bouton loss was the appearance of large numbers of pale presynaptic profiles (PPPs). These were characterized by abnormally tight aggregation of synaptic vesicles and loss of organelles in the boutons. These changes were associated with decreased expression of GAP43 and decreased GAP43 content of synaptosomes. GAP43 is located in membrane rafts of boutons, which is where PrPsc accumulates. It organizes the actin cytoskeleton that is required for synaptic vesicle function. In summary, we are finding that PrPsc accumulation in subcellular compartments is closely associated with functional and morphological abnormalities of neurons and their processes as well as nerve cell death.
AD Stephen J. DeArmond, Essia Bouzamondo-Bernstein, Nako Ishikura, University of California at San Francisco, USA
SP englisch
PO Deutschland