Table 2.

Genetic, RNA interference (RNAi) and proteomic modifier screens

Phenotype	Expressed protein	Tissue	Assay system	Hits	Secondary assays	Ref.
Toxicity	HTT exon 1 Q20 and Q53		Genome-wide loss-of-function enhancer screen in yeast	Genes involved in stress responses, protein folding, and ubiquitin-dependent protein degradation		[84]
Toxicity	HTT exon 1 Q103		Genome-wide loss-of-function suppressor screen in yeast	Genes involved in vacuolar transport, transcriptional regulation/maintenance of chromatin structure, other processes (bna4) and prion genes		[85]
Aggregation	Ade-2 Q25 and Q97		Transposon insertion mutants in yeast	Genes involved in vacuolar transport, transcriptional regulation (Spt4)	Murine striatal neuron cell models of HD	[86]
Toxicity	HTT exon 1 Q2 and Q150	ASH sensory neurons	Mutation screen in Caenorhabditis elegans	polyQ enhancer-1 (pqe-1) gene		[95]
Toxicity	HTT exon 1 Q128	Touch receptor neurons	6034 candidate RNAi screen in C. elegans	Genes involved in cell death, protein folding, intracellular transport, metabolic processes, response to stress, stress-activated pathways	Striatum of HD mouse models	[101]
Aggregation	Q35-YFP	BWM	Genome-wide RNAi in C. elegans	Genes involved in RNA synthesis/processing, protein synthesis, transport, folding, and degradation		[102]
Aggregation	Q35-YFP	BWM	Genome-wide RNAi in C. elegans	Genes involved in cell cycle, DNA and RNA synthesis/processing, energy and metabolism, and protein synthesis, transport and folding	C. elegans expressing Q37-YFP, SODG93A, and temperature sensitive proteins	[105]
Toxicity	Q127	Retina	7000 P-element insertions in Drosophila	DNAJ domain-containing proteins dHDJ1 and dTPR2	Transgenic Drosophila lines	[90]
Toxicity and aggregation	Ataxin-1 Q30 and Q82	Retina, central nervous system	Transposon insertion in Drosophila	Genes involved in protein folding, degradation, transcriptional regulation, RNA binding and stress response		[91]
Toxicity	Ataxin-1 Q82, ataxin-3 Q78 and Q127	Retina	55 modifier strains in Drosophila	Genes involved in protein folding and apoptosis	Drosophila brain	[145]
Toxicity and aggregation	Ataxin-3tr Q78	Retina	2300 enhancer/promoter element insertion library in Drosophila	Chaperones and ubiquitin-pathway components, and genes involved in transcription, translation, and RNA binding	Drosophila model of tau-induced degeneration	[92]
Toxicity and aggregation	HTT588 Q138	Neuronal and non-neuronal tissues	Autosomal deficiency (Df) kit for chromosome II and III (160 Df lines)	Small C-terminal domain phosphatases and Antennapedia complex	Drosophila HD model	[93]
Toxicity	HTT588 Q138 and Q15		Whole genome (468 genes) kinase/phosphatase RNAi sub-library in Drosophila neuronal culture	lkb1	Drosophila HD model	[66]
Toxicity	HTT exon 1 Q97	Mouse brain, mouse muscle	Y2H, MS	Proteins involved in folding, synaptic transmission, cytoskeletal organization, signal transduction, and transcription	Drosophila	[53]
	HTT Q144	Mouse brain	Affinity purification/MS	Proteins involved in translation		[113]
Toxicity	HTT Q97	Mouse brain	Affinity purification/MS	Proteins involved in protein folding, 14-3-3 signaling, microtubule-based intracellular transport, and mitochondrial function	Drosophila	[114]
Toxicity	HTT Q72	iPSC lines	2-DE/MS	Genes involved in oxidative stress and apoptosis		[136]

Blank entry indicates not included in the study.

HTT = huntingtin; HD = Huntington’s disease; YFP = yellow fluorescent protein; BWM = body wall muscle; SOD = superoxide dismutase; TRP2 = tetratricopeptide repeat protein 2; Y2H = yeast 2-hybrid; MS = mass spectrometry; iPSC = inducible pluripotent stem cell; 2-DE = two-dimensional electrophoresis.