Altered dopamine release and monoamine transporters in Vps35 p.D620N knock-in mice.
Altered dopamine release and monoamine transporters in Vps35 p.D620N knock-in mice.
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DOI：
10.1038/s41531-018-0063-3
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Farrer MJ
中科院分区：
文献类型：
--
作者：
Cataldi S;Follett J;Fox JD;Tatarnikov I;Kadgien C;Gustavsson EK;Khinda J;Milnerwood AJ;Farrer MJ
液泡蛋白分选35 （VPS35）是内体膜相关蛋白运输所需的逆转录三聚体的核心组成部分。错义突变Vps35 p.D620N的发现与帕金森病（PD）发病机制中的逆转录功能障碍有关。我们鉴定了一只3月龄时带有Vps35 p.D620N取代的敲入小鼠（以下简称VKI）。标准化行为测试未观察到明显的运动障碍。不同基因型中，酪氨酸羟化酶（TH）阳性的黑质神经元计数和纹状体终末表达具有可比性。快速扫描循环伏安法显示VKI纹状体切片多巴胺释放增加。虽然通过纹状体微透析收集的自由活动动物的细胞外多巴胺在不同基因型之间具有可比性，但多巴胺代谢物与多巴胺的比例表明，VKI纯合子小鼠的多巴胺周转率增加。纹状体蛋白的Western blot显示，尽管与其他突触标志物的变化无关，但多巴胺转运蛋白（DAT）的基因型依赖性减少，同时水泡单胺转运蛋白2 （VMAT2）的基因型增加。免疫组织化学分析进一步证实了DAT的降低。数据显示，VKI小鼠的多巴胺能系统与野生型小鼠相比发生了深刻的变化。我们得出结论，早期突触功能障碍有助于黑质纹状体系统中与年龄相关的病理生理，这可能导致人类帕金森病。一种与迟发性帕金森病（PD）相关的突变破坏了小鼠多巴胺能神经传递。由加拿大英属哥伦比亚大学应用神经遗传学中心的Matthew J. Farrer领导的一项研究，在年轻成年小鼠中检测了编码膜相关蛋白回收所需复合物核心亚基的基因错义突变的影响，液泡蛋白分类35 （VPS35; VPS35）。虽然没有发现对运动功能或神经变性的显著影响，但在突变小鼠中观察到背外侧纹状体多巴胺释放和周转量的增加。多巴胺再摄取和储存所需的转运体的运输和再循环缺陷可能是这些影响的基础。对Vps35突变小鼠的进一步分析可以提高我们对PD神经退行性变之前突触功能障碍的理解。
Vacuolar protein sorting 35 (VPS35) is a core component of the retromer trimer required for endosomal membrane-associated protein trafficking. The discovery of a missense mutation, Vps35 p.D620N implicates retromer dysfunction in the pathogenesis of Parkinson’s disease (PD). We have characterized a knock-in mouse with a Vps35 p.D620N substitution (hereafter referred to as VKI) at 3 months of age. Standardized behavioral testing did not observe overt movement disorder. Tyrosine hydroxylase (TH)-positive nigral neuron counts and terminal expression in striata were comparable across genotypes. Fast scan cyclic voltammetry revealed increased dopamine release in VKI striatal slices. While extracellular dopamine collected via striatal microdialysis of freely moving animals was comparable across genotypes, the ratio of dopamine metabolites to dopamine suggests increased dopamine turnover in VKI homozygous mice. Western blot of striatal proteins revealed a genotype-dependent decrease in dopamine transporter (DAT) along with an increase in vesicular monoamine transporter 2 (VMAT2), albeit independent of changes in other synaptic markers. The reduction in DAT was further supported by immunohistochemical analysis. The data show that the dopaminergic system of VKI mice is profoundly altered relative to wild-type littermates. We conclude early synaptic dysfunction contributes to age-related pathophysiology in the nigrostriatal system that may lead to parkinsonism in man. A mutation linked to late-onset Parkinson’s disease (PD) disrupts dopaminergic neurotransmission in mice. A study led by Matthew J. Farrer at the Centre for Applied Neurogenetics, University of British Columbia, Canada, examined the effects of a missense mutation in the gene encoding a core subunit of a complex required for recycling membrane-associated proteins, Vacuolar Protein Sorting 35 (VPS35; Vps35), in young adult mice. Although no significant effects on motor function or neurodegeneration were found, an increase in dopamine release and turnover in the dorsolateral striatum were observed in the mutant mice. Deficits in the transport and recycling of transporters required for dopamine re-uptake and storage may underlie these effects. Further analyses of Vps35 mutant mice could improve our understanding of the synaptic dysfunction that precedes neurodegeneration in PD.
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DOI：
10.1111/ejn.13357
发表时间：
2017-01
期刊：
The European journal of neuroscience
影响因子：
--
作者：
Lohr KM;Masoud ST;Salahpour A;Miller GW
通讯作者：
Miller GW
DOI：
10.1042/bcj20180248
发表时间：
2018-06-06
期刊：
The Biochemical journal
影响因子：
--
作者：
Mir R;Tonelli F;Lis P;Macartney T;Polinski NK;Martinez TN;Chou MY;Howden AJM;König T;Hotzy C;Milenkovic I;Brücke T;Zimprich A;Sammler E;Alessi DR
通讯作者：
Alessi DR
影响因子：
3.3
作者：
Struhal, Walter;Presslauer, Stefan;Ransmayr, Gerhard
通讯作者：
Ransmayr, Gerhard
DOI：
10.1073/pnas.1402134111
发表时间：
2014-07-08
影响因子：
11.1
作者：
Lohr, Kelly M.;Bernstein, Alison I.;Miller, Gary W.
通讯作者：
Miller, Gary W.
影响因子：
16.2
作者：
MacLeod DA;Rhinn H;Kuwahara T;Zolin A;Di Paolo G;McCabe BD;Marder KS;Honig LS;Clark LN;Small SA;Abeliovich A
通讯作者：
Abeliovich A