Novel Metabolic Abnormalities in the Tricarboxylic Acid Cycle in Peripheral Cells From Huntington's Disease Patients

被引：26

作者：

Naseri, Nima N. ^{[1
]}

Bonica, Joseph ^{[1
]}

Xu, Hui ^{[1
]}

Park, Larry C. ^{[3
]}

Arjomand, Jamshid ^{[3
]}

Chen, Zhengming ^{[2
]}

Gibson, Gary E. ^{[1
]}

机构：

[1] Weill Cornell Med Coll, Brain & Mind Res Inst, Burke Med Res Inst, 785 Mamaroneck Ave, White Plains, NY 10605 USA

[2] Weill Cornell Med Coll, Dept Healthcare Policy & Res, Div Biostat & Epidemiol, 425 East 61st St, New York, NY 10065 USA

[3] CHDI Management CHDI Fdn Inc, 6080 Ctr Dr Suite 100, Los Angeles, CA 90045 USA

来源：

PLOS ONE | 2016年 / 11卷 / 09期

关键词：

KETOGLUTARATE DEHYDROGENASE COMPLEX; PYRUVATE-DEHYDROGENASE; ALPHA-KETOGLUTARATE; PATHOLOGICAL LENGTH; TRANSGENIC MOUSE; ALZHEIMER BRAIN; MITOCHONDRIAL; PROTEIN; MODELS; DAMAGE;

D O I：

10.1371/journal.pone.0160384

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Metabolic dysfunction is well-documented in Huntington's disease (HD). However, the link between the mutant huntingtin (mHTT) gene and the pathology is unknown. The tricarboxylic acid (TCA) cycle is the main metabolic pathway for the production of NADH for conversion to ATP via the electron transport chain (ETC). The objective of this study was to test for differences in enzyme activities, mRNAs and protein levels related to the TCA cycle between lymphoblasts from healthy subjects and from patients with HD. The experiments utilize the advantages of lymphoblasts to reveal new insights about HD. The large quantity of homogeneous cell populations permits multiple dynamic measures to be made on exactly comparable tissues. The activities of nine enzymes related to the TCA cycle and the expression of twenty-nine mRNAs encoding for these enzymes and enzyme complexes were measured. Cells were studied under baseline conditions and during metabolic stress. The results support our recent findings that the activities of the pyruvate dehydrogenase complex (PDHC) and succinate dehydrogenase (SDH) are elevated in HD. The data also show a large unexpected depression in MDH activities. Furthermore, message levels for isocitrate dehydrogenase 1 (IDH1) were markedly increased in in HD lymphoblasts and were responsive to treatments. The use of lymphoblasts allowed us to clarify that the reported decrease in aconitase activity in HD autopsy brains is likely due to secondary hypoxic effects. These results demonstrate the mRNA and enzymes of the TCA cycle are critical therapeutic targets that have been understudied in HD.

引用

页数：17