Protein phosphatase 2Cm-regulated branched-chain amino acid catabolic defect in dorsal root ganglion neurons drives pain sensitization

IF 6.2 2区 医学 Q1 NEUROSCIENCES Acta Neuropathologica Communications Pub Date : 2024-09-10 DOI:10.1186/s40478-024-01856-2
Nan Lian, Fangzhou Li, Cheng Zhou, Yan Yin, Yi Kang, Kaiteng Luo, Su Lui, Tao Li, Peilin Lu
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Abstract

Maladaptive changes of metabolic patterns in the lumbar dorsal root ganglion (DRG) are critical for nociceptive hypersensitivity genesis. The accumulation of branched-chain amino acids (BCAAs) in DRG has been implicated in mechanical allodynia and thermal hyperalgesia, but the exact mechanism is not fully understood. This study aimed to explore how BCAA catabolism in DRG modulates pain sensitization. Wildtype male mice were fed a high-fat diet (HFD) for 8 weeks. Adult PP2Cmfl/fl mice of both sexes were intrathecally injected with pAAV9-hSyn-Cre to delete the mitochondrial targeted 2 C-type serine/threonine protein phosphatase (PP2Cm) in DRG neurons. Here, we reported that BCAA catabolism was impaired in the lumbar 4–5 (L4-L5) DRGs of mice fed a high-fat diet (HFD). Conditional deletion of PP2Cm in DRG neurons led to mechanical allodynia, heat and cold hyperalgesia. Mechanistically, the genetic knockout of PP2Cm resulted in the upregulation of C-C chemokine ligand 5/C-C chemokine receptor 5 (CCL5/CCR5) axis and an increase in transient receptor potential ankyrin 1 (TRPA1) expression. Blocking the CCL5/CCR5 signaling or TRPA1 alleviated pain behaviors induced by PP2Cm deletion. Thus, targeting BCAA catabolism in DRG neurons may be a potential management strategy for pain sensitization.
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背根神经节神经元中由蛋白磷酸酶 2Cm 调节的支链氨基酸分解缺陷驱动痛觉敏感化
腰部背根神经节(DRG)代谢模式的适应性不良变化是痛觉过敏发生的关键。支链氨基酸(BCAAs)在DRG中的积累与机械异感症和热超敏反应有关,但其确切机制尚未完全清楚。本研究旨在探讨DRG中的BCAA分解如何调节痛敏。野生型雄性小鼠以高脂肪饮食(HFD)喂养 8 周。成年的 PP2Cmfl/fl 雌雄小鼠经鞘内注射 pAAV9-hSyn-Cre,以删除 DRG 神经元中的线粒体靶向 2 C 型丝氨酸/苏氨酸蛋白磷酸酶(PP2Cm)。在此,我们报告了高脂饮食(HFD)小鼠腰4-5(L4-L5)DRG中BCAA分解代谢受损的情况。在DRG神经元中条件性缺失PP2Cm会导致机械异感、冷热痛觉减退。从机理上讲,基因敲除PP2Cm会导致C-C趋化因子配体5/C-C趋化因子受体5(CCL5/CCR5)轴上调,并增加瞬时受体电位ankyrin 1(TRPA1)的表达。阻断CCL5/CCR5信号传导或TRPA1可减轻PP2Cm缺失诱发的疼痛行为。因此,针对DRG神经元的BCAA分解可能是一种潜在的痛敏化管理策略。
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来源期刊
Acta Neuropathologica Communications
Acta Neuropathologica Communications Medicine-Pathology and Forensic Medicine
CiteScore
11.20
自引率
2.80%
发文量
162
审稿时长
8 weeks
期刊介绍: "Acta Neuropathologica Communications (ANC)" is a peer-reviewed journal that specializes in the rapid publication of research articles focused on the mechanisms underlying neurological diseases. The journal emphasizes the use of molecular, cellular, and morphological techniques applied to experimental or human tissues to investigate the pathogenesis of neurological disorders. ANC is committed to a fast-track publication process, aiming to publish accepted manuscripts within two months of submission. This expedited timeline is designed to ensure that the latest findings in neuroscience and pathology are disseminated quickly to the scientific community, fostering rapid advancements in the field of neurology and neuroscience. The journal's focus on cutting-edge research and its swift publication schedule make it a valuable resource for researchers, clinicians, and other professionals interested in the study and treatment of neurological conditions.
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