Abnormalities in the Tricarboxylic Acid Cycle in Huntington Disease and in a Huntington Disease Mouse Model

Abstract

Glucose metabolism is reduced in the brains of patients with Huntington disease (HD). The mechanisms underlying this deficit, its link to the pathology of the disease and the vulnerability of the striatum in HD remain unknown. Abnormalities in some of the key mitochondrial enzymes involved in glucose metabolism, including the pyruvate dehydrogenase complex (PDHC) and the tricarboxylic acid (TCA) cycle, may contribute to these deficits. Here, activities for these enzymes and select protein levels were measured in human postmortem cortex and in striatum and cortex of an HD mouse model (Q175); mRNA levels encoding for these enzymes were also measured in the Q175 mouse cortex. The activities of PDHC and nearly all of the TCA cycle enzymes were dramatically lower (−50%–90%) in humans than in mice. The activity of succinate dehydrogenase increased with HD in human (35%) and mouse (23%) cortex. No other changes were detected in the HD cortex or mouse striatum. In Q175 cortex, there were increased activities of PDHC (+12%) and aconitase (+32%). Increased mRNA levels for succinyl thiokinase (+88%) and isocitrate dehydrogenase (+64%), suggested an upregulation of the TCA cycle. These patterns of change differ from those reported in other diseases, which may offer unique metabolic therapeutic opportunities for HD patients.

Circadian dysfunction in the Q175 model of Huntington's disease: Network analysis

“…For example, the liver clock promotes gluconeogenesis and glycogenolysis during the sleep/fasting period, while fostering glycogen and cholesterol synthesis during the wake/feeding period. The CBT measures suggest that the circadian regulation of metabolism is compromised in the Q175 line and fits with prior work that demonstrated that HD patients as well as the Q175 mice have deficits in the tricarboxylic acid cycle (Naseri et al, ) responsible for the production of ATP. The diurnal variation in CBT was also attenuated in the R6/2 (Fisher et al, ) and BACHD mice (Kudo et al, ).…”

“…Like the Q175 mutants, the R6/2 mice also exhibited episodes of hypothermia, particularly evident in the dark period. Overall, there is strong evidence for mitochondrial dysfunction in HD as well as in other neurodegenerative diseases (Carmo, Naia, Lopes, & Rego, ; Dubinsky, ; Franco‐Iborra, Vila, & Perier, ; Kuhl et al, ; Naseri et al, ). Unintended weight loss is a hallmark of HD patients and a recent study found that a high body mass index (BMI) is associated with a significantly slower rate of functional, motor, and cognitive deterioration (van der Burg et al, ).…”

Quantitative Proteomic Analysis Reveals Similarities between Huntington’s Disease (HD) and Huntington’s Disease-Like 2 (HDL2) Human Brains

“…63 In addition, we also found that a subunit of complex II (succinate dehydrogenase), SDHA, subunits of complex III (cytochrome bc 1), UQCRC1 and 2, and a component of cytochrome c oxidase, SCO2 (complex IV), were also less abundant in HD cortex relative to controls. Overall, the observed changes in the protein levels in HD brains are consistent with the current view of the mechanisms of mitochondrial dysfunction in HD, such as a decrease in the enzymes of pyruvate dehydrogenase complex (PDHC), 64 inhibition of the respiratory chain enzymes (described above), increased oxidative stress 65 (superoxide dismutase 1, SOD1, is increased), decrease in brain-specific creatine kinase (CKB), 66 and inhibition of mitochondrial protein import by mutant Htt 67 (TIMM44 and TIMM8A, components of presequence translocase-associated motor complex, PAM, are decreased). The observed changes in six family members of the motor protein kinesin and dynein and changes in abundance of mitochondrial fission factors MFF, MFN2, and FIS1 are also consistent with the idea that mutant Htt may dysregulate mitochondrial dynamics and trafficking.…”

Linking mitochondrial dysfunction, metabolic syndrome and stress signaling in Neurodegeneration

“…Several evidence reports that any alteration in mitochondrial activity propels the pathogenesis of HD; for instance, mtDNA damage and deletion have been reported in HD brains [53]. Significant defects in the enzymes associated with mitochondrial respiratory chain and glucose metabolism, including pyruvate dehydrogenase complex (PDHC), aconitase and succinate dehydrogenase (SDH) have been reported in HD patients [54]. Furthermore, SDH inhibitions by malonate and 3-nitropropionic acid have also reported to cause excessive mitochondrial fission and neuronal death associated with clinical and pathological features of HD [55].…”