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AAV-82Q递送的亨廷顿舞蹈病大鼠模型的优化

An Optimization of AAV-82Q-Delivered Rat Model of Huntington's Disease.

作者信息

So Kyoung-Ha, Choi Jai Ho, Islam Jaisan, Kc Elina, Moon Hyeong Cheol, Won So Yoon, Kim Hyong Kyu, Kim Soochong, Hyun Sang-Hwan, Park Young Seok

机构信息

Institute for Stem Cell & Regenerative Medicine (ISCRM), Veterinary Medical Center and College of Veterinary Medicine, Chungbuk National University, Cheongju, Korea.

Laboratory of Veterinary Embryology and Biotechnology (VETEMBIO), Veterinary Medical Center and College of Veterinary Medicine, Chungbuk National University, Cheongju, Korea.

出版信息

J Korean Neurosurg Soc. 2020 Sep;63(5):579-589. doi: 10.3340/jkns.2019.0182. Epub 2020 Mar 5.

DOI:10.3340/jkns.2019.0182
PMID:32131152
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7477157/
Abstract

OBJECTIVE

No optimum genetic rat Huntington model both neuropathological using an adeno-associated virus (AAV-2) vector vector has been reported to date. We investigated whether direct infection of an AAV2 encoding a fragment of mutant huntingtin (AV2-82Q) into the rat striatum was useful for optimizing the Huntington rat model.

METHODS

We prepared ten unilateral models by injecting AAV2-82Q into the right striatum, as well as ten bilateral models. In each group, five rats were assigned to either the 2×1012 genome copies (GC)/mL of AAV2-82Q (×1, low dose) or 2×1013 GC/mL of AAV2-82Q (×10, high dose) injection model. Ten unilateral and ten bilateral models injected with AAV-empty were also prepared as control groups. We performed cylinder and stepping tests 2, 4, 6, and 8 weeks after injection, tested EM48 positive mutant huntingtin aggregates.

RESULTS

The high dose of unilateral and bilateral AAV2-82Q model showed a greater decrease in performance on the stepping and cylinder tests. We also observed more prominent EM48-positive mutant huntingtin aggregates in the medium spiny neurons of the high dose of AAV2-82Q injected group.

CONCLUSION

Based on the results from the present study, high dose of AAV2-82Q is the optimum titer for establishing a Huntington rat model. Delivery of high dose of human AAV2-82Q resulted in the manifestation of Huntington behaviors and optimum expression of the huntingtin protein in vivo.

摘要

目的

迄今为止，尚无使用腺相关病毒（AAV-2）载体的最佳遗传性大鼠亨廷顿病模型的神经病理学报告。我们研究了将编码突变型亨廷顿蛋白片段的AAV2（AV2-82Q）直接注射到大鼠纹状体中是否有助于优化亨廷顿大鼠模型。

方法

我们通过将AAV2-82Q注射到右侧纹状体中制备了10个单侧模型以及10个双侧模型。在每组中，5只大鼠被分配到2×10¹²基因组拷贝（GC）/mL的AAV2-82Q（×1，低剂量）或2×10¹³GC/mL的AAV2-82Q（×10，高剂量）注射模型。还制备了10个单侧和10个双侧注射AAV空载体的模型作为对照组。在注射后2、4、6和8周进行圆筒和阶梯试验，检测EM48阳性突变型亨廷顿蛋白聚集体。

结果

高剂量的单侧和双侧AAV2-82Q模型在阶梯和圆筒试验中的表现下降更为明显。我们还在高剂量AAV2-82Q注射组的中等棘状神经元中观察到更明显的EM48阳性突变型亨廷顿蛋白聚集体。

结论

基于本研究结果，高剂量的AAV2-82Q是建立亨廷顿大鼠模型的最佳滴度。高剂量人类AAV2-82Q的递送导致亨廷顿病行为的表现以及亨廷顿蛋白在体内的最佳表达。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4005/7477157/0effeba81b3e/jkns-2019-0182f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4005/7477157/9b5086d58c47/jkns-2019-0182f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4005/7477157/ef9d0a7aaf07/jkns-2019-0182f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4005/7477157/aeb334ce21e6/jkns-2019-0182f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4005/7477157/ba7ea44e6fa6/jkns-2019-0182f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4005/7477157/9b05a4a908af/jkns-2019-0182f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4005/7477157/0effeba81b3e/jkns-2019-0182f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4005/7477157/9b5086d58c47/jkns-2019-0182f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4005/7477157/ef9d0a7aaf07/jkns-2019-0182f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4005/7477157/aeb334ce21e6/jkns-2019-0182f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4005/7477157/ba7ea44e6fa6/jkns-2019-0182f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4005/7477157/9b05a4a908af/jkns-2019-0182f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4005/7477157/0effeba81b3e/jkns-2019-0182f6.jpg

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