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

Autor: Chang KH; Department of Neurology, Chang Gung Memorial Hospital-Linkou Medical Center, Chang Gung University School of Medicine, Taoyuan, Taiwan., Cheng ML; Department of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan.; Metabolomics Core Laboratory, Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan.; Clinical Metabolomics Core Core Laboratory, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan., Tang HY; Metabolomics Core Laboratory, Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan., Lin CY; Department of Neurology, Chang Gung Memorial Hospital-Linkou Medical Center, Chang Gung University School of Medicine, Taoyuan, Taiwan.; Institute for Radiological Research, Chang Gung University, Taoyuan, Taiwan., Chen CM; Department of Neurology, Chang Gung Memorial Hospital-Linkou Medical Center, Chang Gung University School of Medicine, Taoyuan, Taiwan.
Jazyk: angličtina
Zdroj: Aging cell [Aging Cell] 2024 Nov; Vol. 23 (11), pp. e14302. Date of Electronic Publication: 2024 Aug 14.
DOI: 10.1111/acel.14302
Abstrakt: 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.
(© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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