Reduced creatine kinase as a central and peripheral biomarker in Huntington's disease

Abstract

A major goal of current clinical research in Huntington’s disease (HD) has been to identify preclinical and manifest disease biomarkers, as these may improve both diagnosis and the power for therapeutic trials. Although the underlying biochemical alterations and the mechanisms of neuronal degeneration remain unknown, energy metabolism defects in HD have been chronicled for many years. We report that the brain isoenzyme of creatine kinase (CK-BB), an enzyme important in buffering energy stores, was significantly reduced in presymptomatic and manifest disease in brain and blood buffy coat specimens in HD mice and HD patients. Brain CK-BB levels were significantly reduced in R6/2 mice by ~18% to ~68% from 21–91 days of age, while blood CK-BB levels were decreased by ~14% to ~44% during the same disease duration. Similar findings in CK-BB levels were observed in the 140 CAG mice from 4–12 months of age, but not at the earliest time point, 2 months of age. Consistent with the HD mice, there was a grade-dependent loss of brain CK-BB that worsened with disease severity in HD patients from ~28% to ~63%, as compared to non-diseased control patients. In addition, CK-BB blood buffy coat levels were significantly reduced in both premanifest and symptomatic HD patients by ~23% and ~39%, respectively. The correlation of CK-BB as a disease biomarker in both CNS and peripheral tissues from HD mice and HD patients may provide a powerful means to assess disease progression and to predict the potential magnitude of therapeutic benefit in this disorder.

Early Alterations of Brain Cellular Energy Homeostasis in Huntington Disease Models

“…However, it is unlikely that the decrease of BB-CK that we observed early in the brain of HD mice and that previous studies reported in HTT transgenic mice and HD patients (42,43) is sufficient to produce accumulation of phosphocreatine. When blocking the activity of both cytosolic and mitochondrial CK in skeletal muscle, the levels of phosphocreatine were only minimally affected but phosphocreatine could no longer serve to regenerate hydrolyzed ATP (44).…”

Truncated Peroxisome Proliferator-Activated Receptor-γ Coactivator 1α Splice Variant Is Severely Altered in Huntington’s Disease

“…It has been shown that the major ATPbuffering and redistributing system in cells, i.e. the creatine kinase/phosphocreatine system, is severely reduced in human HD [27] . In theory, this should put more demand on the ATP-producing systems, such as glycolysis and mitochondria.…”

Dissociated Expression of Mitochondrial and Cytosolic Creatine Kinases in the Human Brain: A New Perspective on the Role of Creatine in Brain Energy Metabolism

“…5 In HD, BCK has also been observed to be reduced, though it is not known whether this is an underlying cause of cell death or a result of disease processes. 6 It is still commonly assumed that the PCr/CK system operates in all cells of the brain. However, there is some evidence that BCK and uMtCK may have quite different cellular distributions.…”