Impaired brain creatine kinase activity in 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.


CONCLUSIONS
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.
Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10065, USA.
S F
SF
Zhang
T
T
Hennessey
L
L
Yang
N N
NN
Starkova
M F
MF
Beal
A A
AA
Starkov
D000818:Animals; D001921:Brain / Q000201:enzymology*; D001923:Brain Chemistry; D002851:Chromatography, High Pressure Liquid; D052276:Creatine Kinase, BB Form / Q000032:analysis / Q000378:metabolism*; D004195:Disease Models, Animal; D006816:Huntington Disease / Q000201:enzymology*; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D010725:Phosphocreatine / Q000032:analysis / Q000378:metabolism
D010725:Phosphocreatine; D052276:Creatine Kinase, BB Form