In Huntington’s Disease (HD) patients, the mHtt allele is translated into a mutated protein (mutant huntingtin, mHTT), which carries an abnormally long glutamine (polyQ) stretch after amino acid 17 close to the N-terminus. Similar to the physiological huntingtin protein (HTT), mHTT is abundant throughout the body, even though degenerative processes are restricted to selective neuronal tissues. In contrast to HTT, mHTT shows a pathological high concentration in cell nuclei. In addition, mHTT-expressing cells develop mHTT-containing protein aggregates in both nucleus and neurites. The presence of the elongated polyQ stretch leads to a disruption of physiological HTT function as well as a toxic gain of function. The pathogenic events in HD concern intracellular transport, gene as well as protein expression, protein degradation pathways, cellular energy metabolism, ion homeostasis, cell signaling and apoptosis.
zQ175DN-KI mice (JAX# 029928) have the mouse Htt exon 1 replaced by the human Htt exon 1 sequence with ~180-220 CAG repeats. Furthermore, the neo cassette of these KI mice was deleted (DN). zQ175DN KI mice show:
- High mHTT levels
- Reduced body weight
- Reduced general health
- Reduced motor skills
Figure 1: Quantification of mHTT by sandwich immunosorbent assay using the MesoScale Discovery platform in the isocortex of 5.5 months old mixed sex zQ175DN KI and WT mice. WT: n = 3; zQ175DN KI: n = 12. Mean + SEM. Unpaired t-test. ***p<0.001.
Figure 2: Beam Walk test of 5.5. months old mixed sex zQ175DN KI and WT mice. Number of slips on a 10 mm square beam. n = 12 per group. Mean + SEM; unpaired t-test. **p<0.01.