Unaltered SNARE complex formation in an in vivo model of prion disease.
The ME7 model of prion disease is a chronic slowly evolving model of neurodegeneration in which cell death is preceded by synaptic dysfunction. Previous studies in cell culture show that accumulation of misfolded prion inhibits the formation of the SNARE complexes involving synaptobrevin, syntaxin and SNAP-25 that play an essential role in neurotransmitter release. Such observations suggest that similar phenomenon may contribute to synaptic dysfunction observed in vivo. We have thus used detergent extraction of hippocampal tissue to investigate the status of SNARE complexes in the ME7 model. In the presence of increasing PrP(Sc) deposition we failed to see a change in the amount of SNARE complexes directly extracted into SDS and resolved by SDS-PAGE. Conversely pre-extraction in Triton X-100, a treatment that promotes SNARE complexes ex vivo, demonstrated a modest reduction in hippocampal SNARE complexes when homogenates were made from tissue at late stage disease. This suggests that accumulated PrP(Sc), or perhaps fibrillar complexes formed of prion only inhibit SNARE complexes that are formed ex vivo following biochemical extraction. Thus the accumulation of PrP(Sc) although deleterious to synaptic function in vivo, does not exert its synaptic effects by disrupting the formation of SNARE complexes that are core to transmitter release.
Asuni
Ayodeji A
AA
School of Biological Sciences, University of Southampton, Bassett Crescent East, Southampton, SO16 7PX, UK.
Cunningham
Colm
C
Vigneswaran
Piranavhan
P
Perry
V Hugh
VH
O'Connor
Vincent
V
D000818:Animals; D004591:Electrophoresis, Polyacrylamide Gel; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D008137:Longitudinal Studies; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000378:metabolism*; D017830:Octoxynol; D018620:PrPSc Proteins / Q000302:isolation & purification / Q000378:metabolism*; D017096:Prion Diseases / Q000378:metabolism*; D017510:Protein Folding; D050765:Qa-SNARE Proteins / Q000302:isolation & purification / Q000378:metabolism; D050683:R-SNARE Proteins / Q000302:isolation & purification / Q000378:metabolism; D050600:SNARE Proteins / Q000302:isolation & purification / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology; D050825:Synaptosomal-Associated Protein 25 / Q000302:isolation & purification / Q000378:metabolism; D014020:Tissue Extracts
D018620:PrPSc Proteins; D050765:Qa-SNARE Proteins; D050683:R-SNARE Proteins; D050600:SNARE Proteins; D050825:Synaptosomal-Associated Protein 25; D014020:Tissue Extracts; D017830:Octoxynol