A mutation in the huntingtin (Htt) gene produces mutant Htt and Huntington's 
disease (HD), a neurodegenerative disorder. HD patients have oxidative damage in 
the brain, but the causes are unclear. Compared with controls, we found brain 
levels of NADPH oxidase (NOX) activity, which produces reactive oxygen species 
(ROS), elevated in human HD postmortem cortex and striatum and highest in 
striatum of presymptomatic individuals. Synaptosome fractions from cortex and 
striatum of HD(140Q/140Q) mice had elevated NOX activity at 3 months of age and 
a further rise at 6 and 12 months compared with synaptosomes of age-matched 
wild-type (WT) mice. High NOX activity in primary cortical and striatal neurons 
of HD(140Q/140Q) mice correlated with more ROS and neurite swellings. These 
features and neuronal cell death were markedly reduced by treatment with NOX 
inhibitors such as diphenyleneiodonium (DPI), apocynin (APO) and VAS2870. The 
rise in ROS levels in mitochondria of HD(140Q/140Q) neurons followed the rise in 
NOX activity and inhibiting only mitochondrial ROS was not neuroprotective. 
Mutant Htt colocalized at plasma membrane lipid rafts with gp91-phox, a 
catalytic subunit for the NOX2 isoform. Assembly of NOX2 components at lipid 
rafts requires activation of Rac1 which was also elevated in HD(140Q/140Q) 
neurons. HD(140Q/140Q) mice bred to gp91-phox knock-out mice had lower NOX 
activity in the brain and in primary neurons, and neurons had normal ROS levels 
and significantly improved survival. These findings suggest that increased NOX2 
activity at lipid rafts is an early and major source of oxidative stress and 
cell death in HD(140Q/140Q) neurons.