Table 1.
Animal models of Huntington’s disease with up to 100 CAG repeats
| Animal model | Construct | Promoter | PolyQ repeat length | Pure repeat length/interruptions | Phenotype | Somatic expansion? | References |
| YAC46 (mouse) | FL human HTT gene within a YAC | HTT | Q46 | 46 mixed CAA/CAG | Increased NMDA-induced Ca + response, but no behavioural or cognitive phenotype | Not reported | [54– 56] |
| HD46 | N-terminal 3 kb of human HTT cDNA | Rat NSE | Q46 | (CAG)n(CAA)(CAG) | Increased incidence of clasping, abnormal gait and abnormal activity- though time-points are not clear. HTT inclusions in cortex and striatum. | Not reported | [57] |
| HD48 | FL human HTT | CMV | Q48 | (CAG)n(CAA)(CAG) | Limb clasping from 8– 24 weeks, hyperactivity from 20 weeks, reduced exploration from 24 weeks. Neuronal loss and fibrillary astrocytosis in the striata. HTT aggregates. | Not reported | [58] |
| HdhQ50 | Chimeric human exon 1/ mouse Htt | Htt | Q50 | (CAG)48(CAA)(CAG) | No behavioural or neuropathological changes observed at 6 months of age. | Not reported | [59, 60] |
| HDQ50 | CAG-only tract knocked into mouse exon 1 | Htt | Q52 | (CAG)50(CAA)(CAG) | No behavioural or pathological changes observed. | Not reported but germline expansion is present. The allelic line HDQ150 has somatic expansion. | [25, 61, 62] |
| Tg51 (rat) | 1962 bp rat Htt cDNA fragment | Htt | Q51 | Not clear | Reduced anxiety from 2 months, impaired coordination from 10 months, nuclear inclusions from 12 months. | Not reported | [63] |
| CAG71 | Chimeric human exon 1/ mouse Htt | Htt | Q71 | (CAG)71 (R42) Arginine residue at position 42 | No behavioural abnormalities. | Not reported | [64, 65] |
| YAC72 (mouse) | Full length human HTT gene within a yeast artificial chromosome | HTT | Q72 | (CAG)n(CAA)(CAG) | Circling and foot-clasping from 9 months, hyperactivity at 7 months, HTT aggregates and striatal degeneration from 12 months. | Not reported | [54, 56, 66] |
| Hdh6/Q72 | Chimeric human exon 1/ mouse Htt | Htt | Q72 | (CAG)n(CAA)(CAG) | Hyperaggressive behaviour from 3 months. No neuropathological changes. | Yes. Multiple tissues. Expansion bias in striatum where > 80% of cells showed expansions greater than+5 CAG. | [67] |
| Htt-Q79 | Chimeric human exon 1/ mouse Htt | Htt | Q77 | (CAG)n(CAA)(CAG) | Aggressive behaviour. Reactive gliosis from 40 weeks, nuclear inclusions in the striatum from 80 weeks. | Yes. Multiple tissues (brain, liver, kidney and stomach). | [68, 69] |
| Hdh4/Q80 | Chimeric human exon 1/ mouse Htt | Htt | Q80 | (CAG)n(CAA)(CAG) | Hyperaggressive behaviour from 3 months. Diffuse nuclear staining in the striatum from 17 weeks, HTT aggregates from 48 weeks. | Yes, high levels observed in the striatum at 24 months. Expansions were also observed in the cortex, cerebellum, hippocampus, hindbrain, spinal cord, olfactory bulb, kidney and eye. | [67, 70– 72] |
| N171-82Q | N-terminal 171 amino acids of human HTT cDNA | Prp | Q82 | (CAG)n(CAA)(CAG) | Motor deficit from 5 months, HTT nuclear inclusions. | Not reported | [73] |
| N586-82Q | N-terminal 586 amino acids of human HTT cDNA | Prp | Q82 | (CAG)n(CAA)(CAG) | Rotarod deficit from 4 months, hyperactivity from 5 months, HTT aggregates and cognitive impairment from 8 months. | Not reported | [74] |
| HD89 | FL human HTT | CMV | Q89 | (CAG)n(CAA)(CAG) | Limb clasping from 8 weeks, hyperactivity from 20 weeks, less exploration from 24 weeks. Neuronal loss and fibrillary astrocytosis in the striata. | Not reported | [58] |
| R6/1-89Q | Human HTT exon 1 | HTT | Q89 | (CAG)n(CAA)(CAG) | Clasping behaviour from 24 weeks, diffuse nuclear staining in cerebral cortex and hippocampus from 11 weeks, body weight loss from 28 weeks. | Yes. Expansions in motor cortex and hippocampus from 9 weeks. | [75] |
| HdhQ92 | Chimeric human exon 1/mouse Htt | Htt | Q92 | (CAG)n(CAA)(CAG) | Cognitive deficits from 4 months, mild motor deficit and HTT aggregates from 6 months, striatal cell loss from 8 months. | Yes, in striatum and liver | [60] |
| CAG94 | Chimeric human exon 1/mouse Htt | Htt | Q94 | (CAG)94 (R42) Arginine residue at position 42 | Increased sensitivity to NMDA from 7 weeks. Increased rearing from 9 weeks, decreased motor and exploratory activity from 18 weeks. | Not reported | [64, 65] |
| Hu97/18 (mouse) | Two full human HTT alleles, one mutant and one wild type | HTT | Q97 | (CAG)n(CAA)(CAG) | Learning and motor deficit from 2 months, progressive cognitive deficits from 6 months, reduced cortical and striatal volume from 12 months. | Not reported | [76, 77] |
| BAC HD (mouse) | FL human HTT | HTT | Q97 | 97 mixed CAA/CAG | Motor deficit at 2 months significant by 6 months, no HTT aggregates. | No | [78– 80] |
| BAC HD (rat) | FL human HTT | HTT | Q97 | 97 mixed CAA/CAG | Motor deficit from 2 months, hypoactivity from 4 months, learning deficit from 6 months. | No | [81– 83] |
| HD100 | N-terminal 3 kb of human HTT cDNA | Rat NSE | Q100 | (CAG)98(CAA)(CAG) | Rotarod impairment, clasping, abnormal gait from 13– 78 weeks. HTT inclusions from 13 weeks. | Not reported | [57] |
| HDQ50 | CAG tract knocked into mouse exon 1 | Htt | Q100 | (CAG)100(CAA)(CAG) | No behavioural or pathological changes observed. | Not reported but germline expansion is present. The allelic line HDQ150 has somatic expansion. | [25, 61, 62] |
NSE, neuron-specific enolase; CMV, cytomegalovirus; PrP, prion gene promoter. Not reported means no data were available. No means somatic expansion was investigated and not seen.