Presynaptic PRRT2 Deficiency Causes Cerebellar Dysfunction and Paroxysmal Kinesigenic Dyskinesia.
Presynaptic PRRT2 Deficiency Causes Cerebellar Dysfunction and Paroxysmal Kinesigenic Dyskinesia.
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DOI：
10.1016/j.neuroscience.2020.08.034
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发表时间：
2020-11-10
期刊：
影响因子：
3.3
通讯作者：
LeDoux, Mark S.
中科院分区：
文献类型：
--
作者：
Calame, Dylan J.;Xiao, Jianfeng;Khan, Mohammad Moshahid;Hollingsworth, T. J.;Xue, Yi;Person, Abigail L.;LeDoux, Mark S.
PRRT 2功能缺失突变与家族性阵发性运动诱发性运动障碍（PKD）、婴儿惊厥和舞蹈手足徐动症以及良性家族性婴儿癫痫发作相关。肌张力障碍是PKD患者最常见的不自主运动障碍。使用lacZ报告基因和定量逆转录酶PCR，我们绘制了PRRT 2在小鼠大脑中的时空分布，并显示在小脑皮质中表达水平最高。对PRRT 2在小脑皮质内定位的进一步研究表明，Prrt 2转录本存在于颗粒细胞中，但不存在于小脑皮质内的浦肯野细胞或中间神经元中，并且PRRT 2在突触前定位于分子层中。通过电子显微镜对小脑分子层突触的分析表明，Prrt 2 −/−小鼠停靠的囊泡数量增加，但总体囊泡数量减少。除了几项运动任务的表现受损外，大约5%的Prrt 2 −/−小鼠表现出明显的PKD，表面有效性表现为肌张力障碍。在Prrt 2突变体中，我们发现平行纤维-浦肯野细胞突触的平行纤维易化减少，浦肯野细胞兴奋性降低，小脑核兴奋性正常，建立了一种潜在的机制，通过这种机制改变小脑活动促进小脑核的去抑制，驱动PKD的运动异常。总的来说，我们的研究结果复制，完善和扩展了以前的工作与PRRT 2小鼠模型，有助于了解神经系统的阵发性疾病，并提供机制洞察小脑皮质功能障碍在肌张力障碍中的作用。
PRRT2 loss-of-function mutations have been associated with familial paroxysmal kinesigenic dyskinesia (PKD), infantile convulsions and choreoathetosis, and benign familial infantile seizures. Dystonia is the foremost involuntary movement disorder manifest by patients with PKD. Using a lacZ reporter and quantitative reverse-transcriptase PCR, we mapped the temporal and spatial distribution of PRRT2 in mouse brain and showed the highest levels of expression in cerebellar cortex. Further investigation into PRRT2 localization within the cerebellar cortex revealed that Prrt2 transcripts reside in granule cells but not Purkinje cells or interneurons within cerebellar cortex, and PRRT2 is presynaptically localized in the molecular layer. Analysis of synapses in the cerebellar molecular layer via electron microscopy showed that Prrt2−/− mice have increased numbers of docked vesicles but decreased vesicle numbers overall. In addition to impaired performance on several motor tasks, approximately 5% of Prrt2−/− mice exhibited overt PKD with clear face validity manifest as dystonia. In Prrt2 mutants, we found reduced parallel fiber facilitation at parallel fiber-Purkinje cell synapses, reduced Purkinje cell excitability, and normal cerebellar nuclear excitability, establishing a potential mechanism by which altered cerebellar activity promotes disinhibition of the cerebellar nuclei, driving motor abnormalities in PKD. Overall, our findings replicate, refine, and expand upon previous work with PRRT2 mouse models, contribute to understanding of paroxysmal disorders of the nervous system, and provide mechanistic insight into the role of cerebellar cortical dysfunction in dystonia.
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影响因子：
--
作者：
Liu YT;Nian FS;Chou WJ;Tai CY;Kwan SY;Chen C;Kuo PW;Lin PH;Chen CY;Huang CW;Lee YC;Soong BW;Tsai JW
通讯作者：
Tsai JW
影响因子：
30.8
作者：
Chen, Wan-Jin;Lin, Yu;Wu, Zhi-Ying
通讯作者：
Wu, Zhi-Ying
影响因子：
--
作者：
GOODENOUGH, DJ;FARIELLO, RG;CHUN, RWM
通讯作者：
CHUN, RWM
影响因子：
8.6
作者：
Chatterjee, A;Louis, ED;Frucht, S
通讯作者：
Frucht, S
DOI：
10.1093/brain/awy051
发表时间：
2018-04-01
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Fruscione F;Valente P;Sterlini B;Romei A;Baldassari S;Fadda M;Prestigio C;Giansante G;Sartorelli J;Rossi P;Rubio A;Gambardella A;Nieus T;Broccoli V;Fassio A;Baldelli P;Corradi A;Zara F;Benfenati F
通讯作者：
Benfenati F