Neuronal overexpression of Alzheimer's disease and Down's syndrome associated DYRK1A/minibrain gene alters motor decline, neurodegeneration and synaptic plasticity in Drosophila.
Neuronal overexpression of Alzheimer's disease and Down's syndrome associated DYRK1A/minibrain gene alters motor decline, neurodegeneration and synaptic plasticity in Drosophila.
复制标题
阿尔茨海默病和唐氏综合症相关的 DYRK1A/小脑基因的神经元过度表达会改变果蝇的运动衰退、神经变性和突触可塑性。
DOI：
10.1016/j.nbd.2019.01.017
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发表时间：
2019
影响因子：
6.1
通讯作者：
Lowe SA
中科院分区：
文献类型：
--
作者：
Lowe SA
唐氏综合征（DS）的特征在于认知和运动发育异常，并且在以后的生活中表现为进行性阿尔茨海默病（AD）样痴呆、神经病理学、运动功能下降和预期寿命缩短。它是由21号染色体三体（Hsa21）引起的，但单个Hsa21基因如何影响疾病的各个方面还不完全清楚。以前的工作已经证明了Hsa21基因DYRK1A在认知和运动缺陷中的作用，以及在DS脑中改变的神经发生和神经退行性变中的作用，但其对其他DS表型的贡献尚不清楚。在这里，我们证明了在果蝇神经系统中，DYRK1A的果蝇直系同源物minibrain（mnb）的过度表达加速了运动能力的年龄依赖性下降和寿命缩短。眼内mnn的过度表达具有神经毒性，而脑内椭球体神经元的过度表达则导致年龄依赖性神经退行性变。在幼虫神经肌肉接头，哺乳动物中枢神经元突触的一个已建立的模型，neuronalmnboverexpression增强自发囊泡递质释放。它还减缓了由高频神经刺激引起的诱发递质释放的短期抑制的恢复，并增加了支配肌肉的两个运动神经元之一的扣结数量。这些结果为进一步了解DYRK1的复制在DS的异常衰老和突触功能障碍中的作用提供了依据。
Down syndrome (DS) is characterised by abnormal cognitive and motor development, and later in life by progressive Alzheimer's disease (AD)-like dementia, neuropathology, declining motor function and shorter life expectancy. It is caused by trisomy of chromosome 21 (Hsa21), but how individual Hsa21 genes contribute to various aspects of the disorder is incompletely understood. Previous work has demonstrated a role for triplication of the Hsa21 geneDYRK1Ain cognitive and motor deficits, as well as in altered neurogenesis and neurofibrillary degeneration in the DS brain, but its contribution to other DS phenotypes is unclear. Here we demonstrate that overexpression ofminibrain(mnb), theDrosophilaortholog ofDYRK1A, in theDrosophilanervous system accelerated age-dependent decline in motor performance and shortened lifespan. Overexpression ofmnbin the eye was neurotoxic and overexpression in ellipsoid body neurons in the brain caused age-dependent neurodegeneration. At the larval neuromuscular junction, an established model for mammalian central glutamatergic synapses, neuronalmnboverexpression enhanced spontaneous vesicular transmitter release. It also slowed recovery from short-term depression of evoked transmitter release induced by high-frequency nerve stimulation and increased the number of boutons in one of the two glutamatergic motor neurons innervating the muscle. These results provide further insight into the roles ofDYRK1Atriplication in abnormal aging and synaptic dysfunction in DS.