Figure 1.

Cystathionine γ-lyase (CSE), the biosynthetic enzyme for cysteine is depleted in Huntington's disease (HD) at the transcriptional level. (A) CSE is a key enzyme in the reverse transsulfuration pathway which generates cysteine from its precursor, cystathionine. Cystathionine is synthesized by cystathionine β-synthase (CBS) by condensing homocysteine derived from dietary methionine with serine. Both CSE and CBS generate the major gasotransmitter hydrogen sulfide (H₂S) from cysteine as well as homocysteine. In addition, cysteine serves as a building block for biosynthesis of the antioxidant glutathione. (B) Under normal conditions, CSE transcription is regulated by the transcription factor specificity protein 1 (SP1) in conjunction with associated coactivators such as TATA box binding protein (TBP), TBP-associated factor 4 (TAF4), subunits of the general transcription factor, transcription factor II D (TFIID). In HD, mutant huntingtin (mHtt)sequesters SP1 leading to a diminished expression of CSE, which results in lowered cysteine levels, elevated oxidative stress and neurodegeneration.