Loss of SNAP-25 and rabphilin 3a in sensory-motor cortex in Huntington's disease.
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG-expansion in the gene encoding the protein huntingtin. The disease is characterized by progressive motor disturbances, cognitive defects, dementia, and weight loss. Using western blotting and immunohistochemistry we have assessed the expression levels and patterns of a number of proteins involved in neurotransmitter release in post-mortem frontal cortex samples from 10 HD cases with different disease grades. We report a loss of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein, synaptosome-associated protein 25 (SNAP 25) in HD brains of grades I-IV. Moreover, in brains of grade III and IV we found a reduction in rabphilin 3a, a protein involved in vesicle docking and recycling. These losses appear to be specific and not due to a general loss of synapses in the HD cortex. Thus, levels of synaptobrevin II, syntaxin 1, rab3a or synaptophysin are unaltered in the same patient samples. SNAP 25 and rabphilin 3a are crucial for neurotransmitter release. Therefore, we suggest that a deficient pre-synaptic transmitter release may underlie some of the symptoms of HD.
Smith
Ruben
R
Neuronal Survival Unit, Wallenberg Neuroscience Center, Lund University, Lund, Sweden. ruben.smith@med.lu.se
Klein
Pontus
P
Koc-Schmitz
Yeliz
Y
Waldvogel
Henry J
HJ
Faull
Richard L M
RL
Brundin
Patrik
P
Plomann
Markus
M
Li
Jia-Yi
JY
D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis / Q000172:deficiency*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005089:Exocytosis / Q000235:genetics; D005260:Female; D005625:Frontal Lobe / Q000737:chemistry* / Q000473:pathology; D006801:Humans; D006816:Huntington Disease / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000172:deficiency*; D012720:Severity of Illness Index; D013003:Somatosensory Cortex / Q000737:chemistry* / Q000473:pathology; D013569:Synapses / Q000473:pathology; D016708:Synaptophysin / Q000032:analysis; D050825:Synaptosomal-Associated Protein 25 / Q000032:analysis / Q000172:deficiency*; D050827:Syntaxin 1 / Q000032:analysis; D050988:Vesicle-Associated Membrane Protein 2 / Q000032:analysis; D033921:Vesicular Transport Proteins / Q000032:analysis / Q000172:deficiency*; D020826:rab3A GTP-Binding Protein / Q000032:analysis; D000097624:Rabphilin-3A
D048868:Adaptor Proteins, Signal Transducing; D009419:Nerve Tissue Proteins; D016708:Synaptophysin; D050825:Synaptosomal-Associated Protein 25; D050827:Syntaxin 1; D050988:Vesicle-Associated Membrane Protein 2; D033921:Vesicular Transport Proteins; D020826:rab3A GTP-Binding Protein; D000097624:Rabphilin-3A; C494208:SNAP25 protein, human