Chronic and acute LRRK2 silencing has no long-term behavioral effects, whereas wild-type and mutant LRRK2 overexpression induce motor and cognitive deficits and altered regulation of dopamine release.
Chronic and acute LRRK2 silencing has no long-term behavioral effects, whereas wild-type and mutant LRRK2 overexpression induce motor and cognitive deficits and altered regulation of dopamine release.
复制标题
慢性和急性 LRRK2 沉默不会产生长期行为影响，而野生型和突变型 LRRK2 过度表达会导致运动和认知缺陷，并改变多巴胺释放的调节。
DOI：
10.1016/j.parkreldis.2015.07.025
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发表时间：
2015
影响因子：
4.1
通讯作者：
A. Milnerwood
中科院分区：
文献类型：
--
作者：
Mattia Volta;Stefano Cataldi;Dayne A Beccano;Lise N. Munsie;Igor Tatarnikov;Patrick Chou;Sabrina Bergeron;Emma Mitchell;R. Lim;Jaskaran Khinda;Alejandro Lloret;C.Frank Bennett;Carmela Paradiso;M. Morari;M. Farrer;A. Milnerwood
帕金森病相关蛋白LRRK2的生殖系沉默不会改变成年小鼠的谷氨酸或多巴胺的释放，但已有报道随着年龄的增长而出现一些探索性异常。相比之下，高水平的人类LRRK2会导致运动改变和认知障碍，并伴随着纹状体多巴胺水平的下降，后者也在G2019S突变小鼠中观察到。对LRRK2KO、过度表达和突变过度表达小鼠的认知和运动行为的比较测试尚未见报道。纹状体注射反义寡核苷酸观察急性LRRK2沉默对大鼠行为学和多巴胺纤维密度的影响。从hG2019S小鼠制备的纹状体突触体评估了多巴胺的囊泡释放及其对D2自身受体刺激的敏感性。结果LRRK2的遗传消融对运动或认知功能没有长期影响。在急性纹状体沉默后，始终没有观察到对行为或多巴胺能纤维密度的影响。相反，12个月大的OE小鼠表现出持续的运动障碍和认知能力恶化；而hG2019S小鼠表现出早期的多动和有效的学习和记忆，随着年龄的增长，运动和认知障碍逐渐减少。G2019S突变不影响囊泡多巴胺的释放，但降低其对D2介导的抑制的敏感性。结论LRRK2沉默在小鼠中具有良好的耐受性，认为帕金森病不是由于LRRK2功能丧失引起的。高水平的WT和G2019S LRRK2会产生相似但在时间上不同的表型，可能会模拟疾病发展的不同阶段。这些数据表明LRRK2功能的获得在帕金森病的发病机制中具有重要意义。
IntroductionGermline silencing of the PD-related protein LRRK2 does not alter glutamate or dopamine release in adult mice, but some exploratory abnormalities have been reported with ageing. Contrastingly, high levels of human LRRK2 cause locomotor alterations and cognitive deficits accompanied by reduced striatal dopamine levels, with the latter also observed in G2019S mutant mice. Comparative cognitive and motor behavioral testing of LRRK2 KO, overexpressor and mutant overexpressor mice has not previously been reported.MethodsParallel, comparative behavioral characterization was performed assessing motor and cognitive abilities. Striatal antisense oligonucleotide injections were conducted to investigate the effects of acute LRRK2 silencing on behavior and dopamine fiber density. Striatal synaptosomes prepared from hG2019S mice assessed vesicular release of dopamine and its sensitivity to D2 autoreceptor stimulation.ResultsGenetic ablation of LRRK2 has no long-term consequences on motor or cognitive function. Consistently, no effects on behavior or dopaminergic fiber density were observed following acute striatal silencing. Conversely, 12-month OE mice show persistent locomotor deficits and worsening of cognitive abilities; whereas, hG2019S mice display early hyperactivity and effective learning and memory that progress to decreased motor and cognitive deficits at older ages. The G2019S mutation does not affect vesicular dopamine release, but decreases its sensitivity to D2-mediated inhibition.ConclusionLRRK2 silencing is well tolerated in mouse, arguing PD does not result from LRRK2 loss of function. High levels of WT and G2019S LRRK2 produce similar but temporally distinct phenotypes, potentially modeling different stages of disease progression. The data implicate gain of LRRK2 function in the pathogenesis of PD.
影响因子：
4.1
作者：
Dächsel JC;Behrouz B;Yue M;Beevers JE;Melrose HL;Farrer MJ
通讯作者：
Farrer MJ