Impaired Brain Creatine Kinase Activity in Huntington’s Disease

Abstract

Background: Huntington’s disease (HD) is associated with impaired energy metabolism in the brain. Creatine kinase (CK) catalyzes ATP-dependent phosphorylation of creatine (Cr) into phosphocreatine (PCr), thereby serving as readily available high-capacity spatial and temporal ATP buffering. Objective: Substantial evidence supports a specific role of the Cr/PCr system in neurodegenerative diseases. In the brain, the Cr/PCr ATP-buffering system is established by a concerted operation of the brain-specific cytosolic enzyme BB-CK and ubiquitous mitochondrial uMt-CK. It is not yet established whether the activity of these CK isoenzymes is impaired in HD. Methods: We measured PCr, Cr, ATP and ADP in brain extracts of 3 mouse models of HD – R6/2 mice, N171-82Q and HdhQ¹¹¹ mice – and the activity of CK in cytosolic and mitochondrial brain fractions from the same mice. Results: The PCr was significantly increased in mouse HD brain extracts as compared to nontransgenic littermates. We also found an approximately 27% decrease in CK activity in both cytosolic and mitochondrial fractions of R6/2 and N171-82Q mice, and an approximately 25% decrease in the mitochondria from HdhQ¹¹¹ mice. Moreover, uMt-CK and BB-CK activities were approximately 63% lower in HD human brain samples as compared to nondiseased controls. Conclusion: Our findings lend strong support to the role of impaired energy metabolism in HD, and point out the potential importance of impairment of the CK-catalyzed ATP-buffering system in the etiology of HD.

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.…”

Neuronal toxicity of efavirenz: a systematic review

“…Second, creatine kinase (CK) concentrations were significantly reduced in the cortex and cerebellum in mice treated with efavirenz [40]. A decrease in CK has been associated with neurodegenerative diseases [41]. Third, efavirenz causes a concentration-dependent mitochondriopathy in human hepatic cells by inhibiting complex 1 of the respirator chain [42].…”

Analysis of creatine kinase activity with evaluation of protein expression under the effect of heat and hydrogen peroxide

“…These detrimental influences of hydrogen peroxide on functional activity of CK are supported by free radical inhibition of tissues specific CK presented by [22]. PCr and CK were found to be slightly decreased in skeletal muscles of mice with deficient cytosolic and mitochondrial CK activity [21]. In Alzheimer's disea se, amyloid beta-peptide which induces generation of free radicals is thought to inhibit the oxidative sensitive enzyme CK and therefore causes neurodegene ration [30].…”

“…Western blotting with the antibodies against CK isoenzyme using cell homogenate from HeLa cells identifies a single band of 43 kDa. Brain homogenates from Alzheimer's patients show a decrease of CK activity by 86%, whereas expression levels of the enzyme were down by 14 % [7,21]. Additional ly it was shown that the exposure of CK isoenzymes in rat tissues (brain, heart, and muscles) to xanthine and xanthine oxidase or hydrogen peroxide resulted in a significant decrease in the activities of CK in a dose dependent fashion [22].…”