Protein oxidation in Huntington disease.

ABSTRACT

Huntington disease (HD) is an inherited neurodegenerative disorder caused by expansion of CAG repeats in the huntingtin gene, affecting initially the striatum and progressively the cortex. Oxidative stress, and consequent protein oxidation, has been described as important to disease progression. This review focuses on recent advances in the field, with a particular emphasis on the identified target proteins and the role that their oxidation has or might have in the pathophysiology of HD. Oxidation and the resulting inactivation and/or degradation of important proteins can explain the impairment of several metabolic pathways in HD. Oxidation of enzymes involved in ATP synthesis can account for the energy deficiency observed. Impairment of protein folding and degradation can be due to oxidation of several heat shock proteins and Valosin-containing protein. Oxidation of two enzymes involved in the vitamin B6 metabolism could result in decreased availability of pyridoxal phosphate, which is a necessary cofactor in transaminations, the kynurenine pathway and the synthesis of glutathione, GABA, dopamine and serotonin, all of which have a key role in HD pathology. In addition, protein oxidation often contributes to oxidative stress, aggravating the molecular damage inside the cell.