FIGURE 1.

Sources of oxidative stress in HD. Decreased levels of antioxidants, cysteine and ascorbate is observed in HD. The cysteine transporter, excitatory amino acid transporter 3 (EAAT3/EAAC1) is dysregulated in HD leading to decreased intake of cysteine. The uptake of the oxidized form of cysteine, cystine, mediated by the ${\text{x}}_{\text{c}}^{-}$ system, composed of the light chain xCT, and the heavy chain 4F2hc, is also reduced, contributing to low cysteine levels. Ascorbate influx via the SVCT2 transporter is also limited in HD, which leads to reduced antioxidant defense in neurons. Deposition of transition metals such as iron (Fe) has been observed both in the cytoplasm and mitochondria, leading to elevated levels of free radicals which can damage cellular components. Mutant huntingtin (mHtt) aggregates both in the nucleus and cytoplasm affecting multiple cellular processes, which include mitochondrial function, autophagy and proteostasis, which leads to elevated oxidative stress. In the nucleus, mHtt sequesters or affects transcription factors, several of which are involved in regulation of antioxidant defense mechanisms, further contributing to redox imbalance in cells. mHtt also affects DNA repair processes, which results in error prone repair and damage.