Xu Jianhua, Wu Xin-Sheng, Sheng Jiansong, Zhang Zhen, Yue Hai-Yuan, Sun Lixin, Sgobio Carmelo, Lin Xian, Peng Shiyong, Jin Yinghui, Gan Lin, Cai Huaibin, Wu Ling-Gang
Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta, Georgia 30912,
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892.
J Neurosci. 2016 Apr 20;36(16):4408-14. doi: 10.1523/JNEUROSCI.3627-15.2016.
α-Synuclein (α-syn) missense and multiplication mutations have been suggested to cause neurodegenerative diseases, including Parkinson's disease (PD) and dementia with Lewy bodies. Before causing the progressive neuronal loss, α-syn mutations impair exocytosis, which may contribute to eventual neurodegeneration. To understand how α-syn mutations impair exocytosis, we developed a mouse model that selectively expressed PD-related human α-syn A53T (h-α-synA53T) mutation at the calyx of Held terminals, where release mechanisms can be dissected with a patch-clamping technique. With capacitance measurement of endocytosis, we reported that h-α-synA53T, either expressed transgenically or dialyzed in the short term in calyces, inhibited two of the most common forms of endocytosis, the slow and rapid vesicle endocytosis at mammalian central synapses. The expression of h-α-synA53Tin calyces also inhibited vesicle replenishment to the readily releasable pool. These findings may help to understand how α-syn mutations impair neurotransmission before neurodegeneration.
α-Synuclein (α-syn) missense or multiplication mutations may cause neurodegenerative diseases, such as Parkinson's disease and dementia with Lewy bodies. The initial impact of α-syn mutations before neuronal loss is impairment of exocytosis, which may contribute to eventual neurodegeneration. The mechanism underlying impairment of exocytosis is poorly understood. Here we report that an α-syn mutant, the human α-syn A53T, inhibited two of the most commonly observed forms of endocytosis, slow and rapid endocytosis, at a mammalian central synapse. We also found that α-syn A53T inhibited vesicle replenishment to the readily releasable pool. These results may contribute to accounting for the widely observed early synaptic impairment caused by α-syn mutations in the progression toward neurodegeneration.
α-突触核蛋白（α-syn）错义突变和倍增突变被认为会导致神经退行性疾病，包括帕金森病（PD）和路易体痴呆。在导致神经元进行性丧失之前，α-syn突变会损害胞吐作用，这可能导致最终的神经退行性变。为了了解α-syn突变如何损害胞吐作用，我们构建了一种小鼠模型，该模型在Held终扣处选择性表达与PD相关的人类α-syn A53T（h-α-synA53T）突变，在此处可以用膜片钳技术剖析释放机制。通过内吞作用的电容测量，我们报告称，转基因表达或在短期内注入终扣中的h-α-synA53T抑制了两种最常见的内吞形式，即哺乳动物中枢突触处的慢速和快速囊泡内吞作用。h-α-synA53T在终扣中的表达也抑制了囊泡向易释放池的补充。这些发现可能有助于理解α-syn突变在神经退行性变之前如何损害神经传递。
α-突触核蛋白（α-syn）错义或倍增突变可能导致神经退行性疾病，如帕金森病和路易体痴呆。α-syn突变在神经元丧失之前的初始影响是胞吐作用受损，这可能导致最终的神经退行性变。胞吐作用受损的潜在机制尚不清楚。在这里，我们报告称，一种α-syn突变体，即人类α-syn A53T，在哺乳动物中枢突触处抑制了两种最常见的内吞形式，即慢速和快速内吞作用。我们还发现α-syn A53T抑制了囊泡向易释放池的补充。这些结果可能有助于解释在神经退行性变进展过程中α-syn突变广泛观察到的早期突触损伤。
