Fig. 5.

Mitochondrially associated mechanisms involved in Huntington’s disease and the potential effect of creatine supplementation. Mutant huntingtin has been proposed to confer toxic effects to neural tissue by a variety of different mechanisms. (1) With respect to mitochondrial dysfunction, mutant huntingtin has been shown to impair the levels of an important cofactor, PGC-1α, which is involved in regulating the expression nuclear genes encoding mitochondrial proteins (NUGEMPs). (2) Reductions in NUGEMPs can potentially lead to a decrease in the overall content and function in mitochondria. (3) As a consequence, these changes can lead to a reduction in ATP levels and enhanced ROS production. (4) Evidence has also shown that ETC complex activities are impaired in postmortem HD brain tissue. Additionally, in animal models, administration of the neurotoxin, 3-NP, inhibits complex II of the ETC, and leads to Huntington’s-like pathogenesis which underscores the importance of mitochondrial dysfunction in HD. Creatine supplementation reduces lesion volume in the mitochondrial toxin (3-NP) models of HD and provides significant neuroprotection. Given the promising neuroprotective effects of creatine found in animal and phase II clinical studies, a phase III clinical trial in HD patients is currently ongoing