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Impaired brain creatine kinase activity in Huntington's disease
S F Zhang1, T Hennessey, L Yang
1Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10065, USA.
Insights
Huntington's disease impairs brain energy metabolism by reducing creatine kinase (CK) activity. This affects the ATP-buffering system, crucial for neuronal function and potentially contributing to HD's development.
Area of Science:
- Neuroscience
- Biochemistry
- Neurodegenerative Diseases
Background:
- Huntington's disease (HD) is linked to impaired brain energy metabolism.
- The creatine kinase (CK) system, comprising creatine (Cr) and phosphocreatine (PCr), is vital for ATP buffering in the brain.
- This system relies on cytosolic BB-CK and mitochondrial uMt-CK enzymes.
Purpose of the Study:
- To investigate whether CK isoenzyme activity is impaired in Huntington's disease.
- To assess the role of the Cr/PCr ATP-buffering system in HD pathogenesis.
Main Methods:
- Analyzed PCr, Cr, ATP, and ADP levels in brain extracts from three mouse models of HD (R6/2, N171-82Q, HdhQ(111)).
- Measured CK activity in cytosolic and mitochondrial brain fractions from these mouse models.
- Compared CK activity in human HD brain samples with non-diseased controls.
Main Results:
- PCr levels were elevated in mouse HD brain extracts.
- CK activity showed a significant decrease (approx. 27%) in cytosolic and mitochondrial fractions of R6/2 and N171-82Q mice.
- Mitochondrial CK activity decreased by approx. 25% in HdhQ(111) mice.
- BB-CK and uMt-CK activities were substantially lower (approx. 63%) in human HD brain samples.
Conclusions:
- Findings support the role of impaired energy metabolism in HD.
- The study highlights the potential significance of impaired CK-catalyzed ATP buffering in the etiology of Huntington's disease.
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 HdhQ(111) 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 HdhQ(111) 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.
