LRRK2 mediates haloperidol-induced changes in indirect pathway striatal projection neurons

IF 9.6 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Chuyu Chen, Meghan Masotti, Nathaniel Shepard, Vanessa Promes, Giulia Tombesi, Daniel Arango, Claudia Manzoni, Elisa Greggio, Sabine Hilfiker, Yevgenia Kozorovitskiy, Loukia Parisiadou
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Abstract

Haloperidol is used to manage psychotic symptoms in several neurological disorders through mechanisms that involve antagonism of dopamine D2 receptors that are highly expressed in the striatum. Significant side effects of haloperidol, known as extrapyramidal symptoms, lead to motor deficits similar to those seen in Parkinson’s disease and present a major challenge in clinical settings. The underlying molecular mechanisms responsible for these side effects remain poorly understood. Parkinson’s disease-associated leucine-rich repeat kinase 2 (LRRK2) has an essential role in striatal physiology and a known link to dopamine D2 receptor signaling. Here, we systematically explore convergent signaling of haloperidol and LRRK2 through pharmacological or genetic inhibition of LRRK2 kinase, as well as knock-in mouse models expressing pathogenic mutant LRRK2 with increased kinase activity. Behavioral assays show that LRRK2 kinase inhibition ameliorates haloperidol-induced motor changes in mice. A combination of electrophysiological and anatomical approaches reveals that LRRK2 kinase inhibition interferes with haloperidol-induced changes, specifically in striatal neurons of the indirect pathway. Proteomic studies and targeted intracellular pathway analyses demonstrate that haloperidol induces a similar pattern of intracellular signaling as increased LRRK2 kinase activity. Our study suggests that LRRK2 kinase plays a key role in striatal dopamine D2 receptor signaling underlying the undesirable motor side effects of haloperidol. This work opens up new therapeutic avenues for dopamine-related disorders, such as psychosis, also furthering our understanding of Parkinson’s disease pathophysiology.

Abstract Image

LRRK2介导氟哌啶醇间接通路纹状体投射神经元的变化
氟哌啶醇通过拮抗纹状体中高度表达的多巴胺D2受体的机制,用于控制几种神经系统疾病的精神病症状。氟哌啶醇的显著副作用,即锥体外系症状,导致与帕金森病类似的运动缺陷,这是临床环境中的一个重大挑战。导致这些副作用的潜在分子机制仍然知之甚少。帕金森病相关的富亮氨酸重复激酶2 (LRRK2)在纹状体生理中起重要作用,并与多巴胺D2受体信号传导有关。在这里,我们系统地探索了氟哌啶醇和LRRK2的会聚信号,通过药理学或遗传抑制LRRK2激酶,以及敲入小鼠模型表达致病性突变体LRRK2激酶活性增加。行为学实验表明,LRRK2激酶抑制可改善氟哌啶醇诱导的小鼠运动改变。电生理和解剖学方法的结合表明,LRRK2激酶抑制干扰氟哌啶醇诱导的变化,特别是在间接途径的纹状体神经元中。蛋白质组学研究和靶向细胞内通路分析表明,氟哌啶醇诱导的细胞内信号传导模式与增加的LRRK2激酶活性相似。我们的研究表明,LRRK2激酶在纹状体多巴胺D2受体信号传导中起关键作用,这是氟哌啶醇不良运动副作用的基础。这项工作为多巴胺相关疾病如精神病开辟了新的治疗途径,也进一步加深了我们对帕金森氏病病理生理学的理解。
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来源期刊
Molecular Psychiatry
Molecular Psychiatry 医学-精神病学
CiteScore
20.50
自引率
4.50%
发文量
459
审稿时长
4-8 weeks
期刊介绍: Molecular Psychiatry focuses on publishing research that aims to uncover the biological mechanisms behind psychiatric disorders and their treatment. The journal emphasizes studies that bridge pre-clinical and clinical research, covering cellular, molecular, integrative, clinical, imaging, and psychopharmacology levels.
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