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体内PET成像揭示早期帕金森病LRRK2-R1441C大鼠模型背侧纹状体中多巴胺D2受体上调

Dopamine D2 receptor upregulation in dorsal striatum in the LRRK2-R1441C rat model of early Parkinson's disease revealed by in vivo PET imaging.

作者信息

Delgado-Goñi Teresa, Connor-Robson Natalie, Cioroch Milena, Paisey Stephen, Marshall Christopher, Lane Emma L, Hauton David, McCullagh James, Magill Peter J, Cragg Stephanie J, Mackay Clare E, Wade-Martins Richard, Klein Johannes C

机构信息

Oxford Parkinson's Disease Centre (OPDC), University of Oxford, Oxford, UK.

Department of Psychiatry, University of Oxford, Oxford, UK.

出版信息

Sci Rep. 2025 May 7;15(1):15943. doi: 10.1038/s41598-025-99580-x.

DOI:10.1038/s41598-025-99580-x
PMID:40335575
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12059153/
Abstract

We conducted PET imaging with [F]FDOPA and dopamine D2/3 receptor ligand [F]fallypride in aged transgenic rats carrying human pathogenic LRRK2 R1441C or G2019S mutations. These rats have mild age-dependent deficits in dopamine release restricted to dorsal striatum despite no overt loss of dopamine neurons or dopamine content and demonstrate L-DOPA-responsive movement deficits.LRRK2 mutant rats displayed no deficit in [F]FDOPA uptake, consistent with intact dopamine synthesis in striatal axons. However, LRRK2-R1441C rats demonstrated greater binding of [F]fallypride than LRRK2-G2019S or non-transgenic controls, from a regionally selective increase in dorsal striatum. Immunocytochemical labelling post-mortem confirmed a greater density of D2 receptors in LRRK2-R1441C than other genotypes restricted to dorsal striatum, consistent with upregulation of D2-receptors as a compensatory response to the greater dopamine release deficit previously demonstrated in this genotype.These results show that [F]fallypride PET imaging is sensitive to dysregulation of dopamine signalling in the LRRK2-R1441C rat, revealing upregulation of D2 receptors that parallels observations in human putamen in early sporadic PD. Future studies of candidate therapies could exploit this non-invasive approach to assess treatment efficacy.

摘要

我们对携带人类致病性LRRK2 R1441C或G2019S突变的老年转基因大鼠进行了[F]FDOPA和多巴胺D2/3受体配体[F]氟哌利多的PET成像。尽管多巴胺神经元或多巴胺含量没有明显损失，但这些大鼠在多巴胺释放方面存在轻度的年龄依赖性缺陷，仅限于背侧纹状体，并表现出对左旋多巴有反应的运动缺陷。LRRK2突变大鼠在[F]FDOPA摄取方面没有缺陷，这与纹状体轴突中完整的多巴胺合成一致。然而，与LRRK2-G2019S或非转基因对照相比，LRRK2-R1441C大鼠显示出[F]氟哌利多的结合更强，这是由于背侧纹状体区域选择性增加所致。死后免疫细胞化学标记证实，LRRK2-R1441C大鼠背侧纹状体中D2受体的密度高于其他基因型，这与D2受体上调作为对该基因型先前证明的更大多巴胺释放缺陷的代偿反应一致。这些结果表明，[F]氟哌利多PET成像对LRRK2-R1441C大鼠多巴胺信号失调敏感，揭示了D2受体上调，这与早期散发性帕金森病患者壳核中的观察结果相似。未来对候选疗法的研究可以利用这种非侵入性方法来评估治疗效果。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ada6/12059153/5c78ed09ef05/41598_2025_99580_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ada6/12059153/87747cb2ef82/41598_2025_99580_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ada6/12059153/cd19165cad06/41598_2025_99580_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ada6/12059153/79d146e336d8/41598_2025_99580_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ada6/12059153/5c78ed09ef05/41598_2025_99580_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ada6/12059153/87747cb2ef82/41598_2025_99580_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ada6/12059153/cd19165cad06/41598_2025_99580_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ada6/12059153/79d146e336d8/41598_2025_99580_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ada6/12059153/5c78ed09ef05/41598_2025_99580_Fig4_HTML.jpg

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