Nigrostriatal overabundance of α-synuclein leads to decreased vesicle density and deficits in dopamine release that correlate with reduced motor activity
Nigrostriatal overabundance of α-synuclein leads to decreased vesicle density and deficits in dopamine release that correlate with reduced motor activity
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DOI：
10.1007/s00401-012-0963-y
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发表时间：
2012-05-01
影响因子：
12.7
通讯作者：
Schneider, Bernard Laurent
中科院分区：
文献类型：
--
作者：
Gaugler, Meret Nora;Genc, Ozgur;Schneider, Bernard Laurent
α-突触核蛋白（α-syn）是一种存在于大多数神经末梢的突触前蛋白，但其功能在很大程度上仍然未知。与α-syn基因位点倍增相关的帕金森病的家族形式表明，这种蛋白质的过量可能对多巴胺能传递产生有害影响。为了研究这一假设，我们使用腺相关病毒（AAV）载体在大鼠黑质中过表达人α-syn。野生型（WT）或A30 P α-syn的中度过表达在诱导的运动表型上不同，只有WT形式产生偏侧帕金森病损伤。野生型α-syn引起纹状体中多巴胺释放的减少，其超过多巴胺能神经元、轴突纤维的损失和总多巴胺的减少。在超微结构水平上，多巴胺释放的减少对应于纹状体终末多巴胺能囊泡和突触接触密度的降低。有趣的是，膜结合缺陷的A30 P突变体既不显着减少多巴胺的释放，也不引起多巴胺能轴突的超微结构变化，表明α-syn的膜结合特性是至关重要的参与突触前缺陷。为了进一步确定蛋白质对膜的亲和力是否决定了运动缺陷的程度，我们比较了导致明显变性的条件下的三种形式的α-syn。虽然膜结合α-syns（野生型和A53 T）诱导严重的运动障碍，N-末端缺失形式与膜减弱的亲和力是无效的诱导运动缺陷。总之，这些结果表明，α-syn过量是有害的多巴胺神经传递在黑质纹状体多巴胺能轴突的退化的早期阶段。
alpha-Synuclein (alpha-syn) is a presynaptic protein present at most nerve terminals, but its function remains largely unknown. The familial forms of Parkinson's disease associated with multiplications of the alpha-syn gene locus indicate that overabundance of this protein might have a detrimental effect on dopaminergic transmission. To investigate this hypothesis, we use adeno-associated viral (AAV) vectors to overexpress human alpha-syn in the rat substantia nigra. Moderate overexpression of either wild-type (WT) or A30P alpha-syn differs in the motor phenotypes induced, with only the WT form generating hemiparkinsonian impairments. Wild-type alpha-syn causes a reduction of dopamine release in the striatum that exceeds the loss of dopaminergic neurons, axonal fibers, and the reduction in total dopamine. At the ultrastructural level, the reduced dopamine release corresponds to a decreased density of dopaminergic vesicles and synaptic contacts in striatal terminals. Interestingly, the membrane-binding-deficient A30P mutant does neither notably reduce dopamine release nor it cause ultrastructural changes in dopaminergic axons, showing that alpha-syn's membrane-binding properties are critically involved in the presynaptic defects. To further determine if the affinity of the protein for membranes determines the extent of motor defects, we compare three forms of alpha-syn in conditions leading to pronounced degeneration. While membrane-binding alpha-syns (wild-type and A53T) induce severe motor impairments, an N-terminal deleted form with attenuated affinity for membranes is inefficient in inducing motor defects. Overall, these results demonstrate that alpha-syn overabundance is detrimental to dopamine neurotransmission at early stages of the degeneration of nigrostriatal dopaminergic axons.