Figure 2.

Huntingtin- lowering approaches: Along the process from htt DNA transcription via RNA processing and translation to protein folding and function, several well-defined points of interference are possible that ultimately result in lower levels of total or mutated htt protein. Strategies that aim at the protein level (C), i.e., by means of induction of autophagy rely on the hypothesis that HD is mainly a proteinopathy that results from disturbed function and neurotoxic accumulation of mutant htt protein. In contrast, gene expression modification strategies (B) inhibit the generation of the protein, but also may be suitable to cover pathologic aspects on the RNA level that may significantly contribute to HD pathogenesis. (A) Genome editing via, i.e., CRISPR/Cas9 may permanently correct mutant HTT. Correction of the CAG Repeat expansion may have additional beneficial effects since the length of the uninterrupted CAG repeat length on DNA level is inversely correlated to disease onset (for references see text). Altering metagenomic structure by HDAC inhibition, or using Zink Finger transcription factors can inhibit transcription of mutant DNA to mRNA. PCT: PTC Therapeutics; LC3: autophagosome protein microtubule-associated protein 1A/1B light chain 3.