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胆碱代谢失调与胞磷胆碱在亨廷顿病中的治疗潜力。

Dysregulation of choline metabolism and therapeutic potential of citicoline in Huntington's disease.

机构信息

Department of Neurology, Chang Gung Memorial Hospital-Linkou Medical Center, Chang Gung University School of Medicine, Taoyuan, Taiwan.

Department of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan.

出版信息

Aging Cell. 2024 Nov;23(11):e14302. doi: 10.1111/acel.14302. Epub 2024 Aug 14.

DOI:10.1111/acel.14302
PMID:39143698
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11561662/
Abstract

Huntington's disease (HD) is associated with dysregulated choline metabolism, but the underlying mechanisms remain unclear. This study investigated the expression of key enzymes in this pathway in R6/2 HD mice and human HD postmortem brain tissues. We further explored the therapeutic potential of modulating choline metabolism for HD. Both R6/2 mice and HD patients exhibited reduced expression of glycerophosphocholine phosphodiesterase 1 (GPCPD1), a key enzyme in choline metabolism, in the striatum and cortex. The striatum of R6/2 mice also showed decreased choline and phosphorylcholine, and increased glycerophosphocholine, suggesting disruption in choline metabolism due to GPCPD1 deficiency. Treatment with citicoline significantly improved motor performance, upregulated anti-apoptotic Bcl2 expression, and reduced oxidative stress marker malondialdehyde in both brain regions. Metabolomic analysis revealed partial restoration of disrupted metabolic patterns in the striatum and cortex following citicoline treatment. These findings strongly suggest the role of GPCPD1 deficiency in choline metabolism dysregulation in HD. The therapeutic potential of citicoline in R6/2 mice highlights the choline metabolic pathway as a promising target for future HD therapies.

摘要

亨廷顿病（HD）与胆碱代谢失调有关，但潜在机制仍不清楚。本研究调查了 R6/2 HD 小鼠和人类 HD 尸检脑组织中该途径关键酶的表达。我们进一步探讨了调节胆碱代谢治疗 HD 的潜力。R6/2 小鼠和 HD 患者的纹状体和皮质中，胆碱代谢的关键酶甘油磷酸胆碱磷酸二酯酶 1（GPCPD1）的表达均降低。R6/2 小鼠的纹状体还表现出胆碱和磷酸胆碱减少，甘油磷酸胆碱增加，提示由于 GPCPD1 缺乏导致胆碱代谢紊乱。胞磷胆碱治疗显著改善了运动表现，上调了抗凋亡 Bcl2 表达，并降低了两个脑区的氧化应激标志物丙二醛。代谢组学分析表明，胞磷胆碱治疗后纹状体和皮质中破坏的代谢模式部分得到了恢复。这些发现强烈表明 GPCPD1 缺乏在 HD 中胆碱代谢失调中的作用。胞磷胆碱在 R6/2 小鼠中的治疗潜力突出了胆碱代谢途径作为未来 HD 治疗的有希望的靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b2ea/11561662/c8da14f23055/ACEL-23-e14302-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b2ea/11561662/30bc287e3ff2/ACEL-23-e14302-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b2ea/11561662/688b8d4ee3a3/ACEL-23-e14302-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b2ea/11561662/4942f456d1fe/ACEL-23-e14302-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b2ea/11561662/8c1fb8247635/ACEL-23-e14302-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b2ea/11561662/491963c810ad/ACEL-23-e14302-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b2ea/11561662/32fa6b5a113c/ACEL-23-e14302-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b2ea/11561662/c8da14f23055/ACEL-23-e14302-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b2ea/11561662/30bc287e3ff2/ACEL-23-e14302-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b2ea/11561662/688b8d4ee3a3/ACEL-23-e14302-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b2ea/11561662/4942f456d1fe/ACEL-23-e14302-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b2ea/11561662/8c1fb8247635/ACEL-23-e14302-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b2ea/11561662/491963c810ad/ACEL-23-e14302-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b2ea/11561662/32fa6b5a113c/ACEL-23-e14302-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b2ea/11561662/c8da14f23055/ACEL-23-e14302-g008.jpg

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