Figure 7.

Reduced activity of proteases improves motor dysfunction in HD Drosophila model. (A) Table summarizing the effects caused by modulating the levels of the indicated proteases on NT-Htt[128Q]-induced motor performance in Drosophila. Columns 1 and 2 list the human proteases and Drosophila homologs; column 3 shows the amino acid sequence similarity as the blast E-value; column 4 indicates the specific allele tested; column-5 shows the allele class: inducible RNAi constructs (RNAi), loss of function caused by insertion of transposable element (LOF) or overexpression caused by an activating transposable element (OE); column-6 reveals the suppressor (S) or enhancer (E) effect of each allele on NT-Htt[128Q]-induced motor deficits. (B-K) Quantification of motor performance as a function of age in flies of the indicated genotypes using a climbing assay. Control animals expressing just the Elav-Gal4 driver perform well in the climbing assay beyond 14 days (Control-blue dashed line). Flies expressing NT-Htt[128Q] in the nervous system either alone or together with a control RNAi, show progressive motor dysfunction when compared with controls (NT-Htt[128Q] and NT-Htt[128Q]/UAS-white^RNAi, respectively. Black dashed lines). Flies expressing NT-Htt[128Q] in the nervous system but with decreased levels of the proteases: CalpA (CAPN5 homolog, B-C); Sol (CAPN7 homolog, E); Spp (IMP5 homolg, F); CG17370 (IMP5 homolg, G-H); Dm2-MMP (MMP homolog, I-J) or Gol (RNF18 homolog, K) show improved motor performance (Red solid line in B-C and E-H). In contrast, flies expressing NT-Htt[128Q] with increased levels of the protease Sol (CAPN7 homolog) display a worse motor performance (red solid line in D). Data was analyzed using ANOVA followed by Tukey’s hsd. Error bars represent s.e.m. * p<0.01, ** p<0.001, ***p<0.0001. Flies were raised at 26.5°C.