Retromer-dependent neurotransmitter receptor trafficking to synapses is altered by the Parkinson's disease VPS35 mutation p.D620N
Retromer-dependent neurotransmitter receptor trafficking to synapses is altered by the Parkinson's disease VPS35 mutation p.D620N
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DOI：
10.1093/hmg/ddu582
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发表时间：
2015-03-15
影响因子：
3.5
通讯作者：
Farrer, M. J.
中科院分区：
文献类型：
--
作者：
Munsie, L. N.;Milnerwood, A. J.;Farrer, M. J.
液泡蛋白分选 35 (VPS35) 是逆转录酶复合物的核心成分，对于内体蛋白分选和细胞内运输至关重要。我们最近将 VPS35 (p.D620N) 的突变与家族性帕金森病联系起来。在这里，我们表征了成熟小鼠神经元培养物中的人类 VPS35 和逆转录酶功能，并研究了 p.D620N 突变的神经元特异性后果。我们发现 VPS35 定位于树突棘，并参与兴奋性 AMPA 型谷氨酸受体 (AMPAR) 的运输。 VPS35 过表达会改变基本神经元过程，包括兴奋性突触传递、AMPAR 表面表达和突触再循环。 VPS35 p.D620N 在小鼠皮质神经元和由人 p.D620N 携带者的诱导多能干细胞产生的多巴胺神经元样细胞中调节突触传递和 AMPAR 回收的 VPS35 活性充当功能丧失突变。这种对突触功能的干扰可能会对神经元回路产生慢性病理生理应激，从而可能导致这种形式和其他形式的帕金森病的神经变性。
Vacuolar protein sorting 35 (VPS35) is a core component of the retromer complex, crucial to endosomal protein sorting and intracellular trafficking. We recently linked a mutation in VPS35 (p.D620N) to familial parkinsonism. Here, we characterize human VPS35 and retromer function in mature murine neuronal cultures and investigate neuron-specific consequences of the p.D620N mutation. We find VPS35 localizes to dendritic spines and is involved in the trafficking of excitatory AMPA-type glutamate receptors (AMPARs). Fundamental neuronal processes, including excitatory synaptic transmission, AMPAR surface expression and synaptic recycling are altered by VPS35 overexpression. VPS35 p.D620N acts as a loss-of-function mutation with respect to VPS35 activity regulating synaptic transmission and AMPAR recycling in mouse cortical neurons and dopamine neuron-like cells produced from induced pluripotent stem cells of human p.D620N carriers. Such perturbations to synaptic function likely produce chronic pathophysiological stress upon neuronal circuits that may contribute to neurodegeneration in this, and other, forms of parkinsonism.