Abnormalities in the synaptic vesicle fusion machinery in Huntington's disease.
We have recently described the progressive and selective loss of the presynaptic protein complexin II in brains of mice (R6/2) transgenic for the Huntington's disease (HD) mutation. Here we have determined the expression of components of the synaptic vesicle fusion machinery in the striatum and hippocampus from post-mortem brains of HD cases and neurologically normal controls. As in the brains of R6/2 mice, complexin II was markedly depleted in the HD striatum; the depletion was compartmentally organized, with complexin II-poor regions corresponding with areas of low immunoreactivity toward the matrix marker calbindin D(28K). Decreases in the levels of the soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor (SNARE) protein synaptobrevin 2 and of rab3A were also seen, but none of the other proteins tested was significantly affected. In the hippocampus, levels of complexin II, synaptobrevin 2, rab3A, and also of alpha-SNAP, were markedly elevated in HD brains. We suggest that the observed abnormalities in the expression of proteins known to be involved in the control of neurotransmitter release, including both modulators and core components of the vesicle fusion machinery, might account for at least some of the functional abnormalities seen in HD.
Morton
A J
AJ
Department of Pharmacology, University of Cambridge, Cambridge, UK. ajm41@cam.ac.uk
Faull
R L
RL
Edwardson
J M
JM
D033942:Adaptor Proteins, Vesicular Transport; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D064026:Calbindins; D005089:Exocytosis / Q000502:physiology*; D005260:Female; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015151:Immunoblotting; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D017072:Neostriatum / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism; D017729:Presynaptic Terminals / Q000378:metabolism* / Q000473:pathology; D050683:R-SNARE Proteins; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D050600:SNARE Proteins; D013570:Synaptic Membranes / Q000378:metabolism* / Q000473:pathology; D009435:Synaptic Transmission / Q000502:physiology; D013572:Synaptic Vesicles / Q000378:metabolism* / Q000473:pathology; D013574:Synaptosomes / Q000378:metabolism; D033921:Vesicular Transport Proteins
D033942:Adaptor Proteins, Vesicular Transport; D064026:Calbindins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D050683:R-SNARE Proteins; D064030:S100 Calcium Binding Protein G; D050600:SNARE Proteins; D033921:Vesicular Transport Proteins; C095993:complexin II