科研之友
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摘要
Background: The pathogenesis of Parkinson's disease (PD) and dementia with Lewy bodies (DLB) is associated with the accumulation of aggregated forms of the alpha synuclein (alpha SN) protein. An early event in the neuropathology of PD and DLB is the loss of synapses and a corresponding reduction in the level of synaptic proteins. However, the molecular mechanisms involved in synapse damage in these diseases are poorly understood. In this study the process of synapse damage was investigated by measuring the amount of synaptophysin, a pre-synaptic membrane protein essential for neurotransmission, in cultured neurons incubated with alpha SN, or with amyloid-beta (A) peptides that are thought to trigger synapse degeneration in Alzheimer's disease. Results: We report that the addition of recombinant human alpha SN reduced the amount of synaptophysin in cultured cortical and hippocampal neurons indicative of synapse damage. alpha SN also reduced synaptic vesicle recycling, as measured by the uptake of the fluorescent dye FM1-43. These effects of alpha SN on synapses were modified by interactions with other proteins. Thus, the addition of beta SN reduced the effects of alpha SN on synapses. In contrast, the addition of amyloid-beta (A beta)(1-42) exacerbated the effects of alpha SN on synaptic vesicle recycling and synapse damage. Similarly, the addition of alpha SN increased synapse damage induced by A beta(1-42). However, this effect of alpha SN was selective as it did not affect synapse damage induced by the prion-derived peptide PrP82-146. Conclusions: These results are consistent with the hypothesis that oligomers of alpha SN trigger synapse damage in the brains of Parkinson's disease patients. Moreover, they suggest that the effect of alpha SN on synapses may be influenced by interactions with other peptides produced within the brain.
- 出版日期2010-12-7
