Defective Branched-Chain Amino Acid Catabolism in Dorsal Root Ganglia Contributes to Mechanical Pain. Defective Branched-Chain Amino Acid Catabolism in Dorsal Root Ganglia Contributes to Mechanical Pain

Impaired branched-chain amino acid (BCAA) catabolism has recently been implicated in the development of mechanical pain, but the underlying molecular mechanisms are unclear. Here we report that defective BCAA catabolism in dorsal root ganglion (DRG) neurons sensitizes mice to mechanical pain by increasing lactate production and expression of the mechanotransduction channel Piezo2. In high-fat diet-fed obese mice, we observe downregulation of PP2Cm, a key regulator of the BCAA catabolic pathway, in DRG neurons. Mice with conditional knockout of PP2Cm in DRG neurons exhibit mechanical allodynia under normal or SNI-induced neuropathic injury conditions. Furthermore, the VAS scores in the plasma of patients with peripheral neuropathic pain are positively correlated with BCAA contents. Mechanistically, defective BCAA catabolism in DRG neurons promotes lactate production through glycolysis, which increases H3K18la modification and drives Piezo2 expression. Inhibition of lactate production or Piezo2 silencing attenuates the pain phenotype of knockout mice in response to mechanical stimuli. Therefore, our study demonstrates a causal role of defective BCAA catabolism in mechanical pain by enhancing metabolite-mediated epigenetic regulation. Overall design: Cut-tag for H3K18la in mouse DRG neurons

支链氨基酸（branched-chain amino acid, BCAA）代谢受损近来被证实与机械性疼痛的发生密切相关，但其潜在分子机制尚未阐明。本研究发现，背根神经节（dorsal root ganglion, DRG）神经元的BCAA代谢缺陷可通过增加乳酸生成与机械门控通道Piezo2（mechanotransduction channel Piezo2）的表达，使小鼠对机械性疼痛的敏感性显著升高。在高脂饮食喂养的肥胖小鼠中，我们观察到其DRG神经元内PP2Cm——BCAA代谢通路的关键调控因子——的表达水平显著下调。DRG神经元中PP2Cm条件性敲除的小鼠，在正常生理状态或坐骨神经分支损伤（spared nerve injury, SNI）诱导的神经性损伤模型下，均表现出机械性痛觉超敏。此外，周围神经性疼痛患者血浆的视觉模拟评分法（Visual Analogue Scale, VAS）评分与BCAA含量呈正相关。机制研究表明，DRG神经元的BCAA代谢缺陷可通过激活糖酵解通路促进乳酸生成，乳酸可上调组蛋白H3赖氨酸18乳酰化（H3K18la）修饰水平，进而驱动Piezo2的基因表达。抑制乳酸生成或沉默Piezo2基因，均可缓解PP2Cm条件性敲除小鼠对机械刺激的痛觉异常表型。综上，本研究证实了BCAA代谢缺陷可通过增强代谢物介导的表观遗传调控，在机械性疼痛的发生发展中发挥因果性作用。整体实验设计：在小鼠DRG神经元中针对H3K18la开展Cut-tag检测。