Novel Metabolic Abnormalities in the Tricarboxylic Acid Cycle in Peripheral Cells From Huntington's Disease Patients.
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.
Weill Cornell Medical College, Brain and Mind Research Institute, Burke Medical Research Institute, 785 Mamaroneck Avenue, White Plains, NY 10605, United States of America.
Nima N
NN
Naseri
Weill Cornell Medical College, Brain and Mind Research Institute, Burke Medical Research Institute, 785 Mamaroneck Avenue, White Plains, NY 10605, United States of America.
Joseph
J
Bonica
Weill Cornell Medical College, Brain and Mind Research Institute, Burke Medical Research Institute, 785 Mamaroneck Avenue, White Plains, NY 10605, United States of America.
Hui
H
Xu
CHDI Management/CHDI Foundation, Inc., 6080 Center Drive. Suite 100, Los Angeles, CA 90045, United States of America.
Larry C
LC
Park
CHDI Management/CHDI Foundation, Inc., 6080 Center Drive. Suite 100, Los Angeles, CA 90045, United States of America.
Jamshid
J
Arjomand
Weill Cornell Medical College, Division of Biostatistics and Epidemiology, Department of Healthcare Policy and Research, 425 East 61st Street, New York, NY 10065, United States of America.
Zhengming
Z
Chen
Weill Cornell Medical College, Brain and Mind Research Institute, Burke Medical Research Institute, 785 Mamaroneck Avenue, White Plains, NY 10605, United States of America.
Gary E
GE
Gibson
D000328:Adult; D016022:Case-Control Studies; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D002952:Citric Acid Cycle; D004734:Energy Metabolism; D005260:Female; D015870:Gene Expression; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D011768:Pyruvate Dehydrogenase Complex / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012966:Sodium Cyanide / Q000494:pharmacology; D013312:Stress, Physiological; D018911:Trinucleotide Repeats
D011768:Pyruvate Dehydrogenase Complex; D012333:RNA, Messenger; D012966:Sodium Cyanide