Some of the most accurate mouse models of PolyQ disease
| Disease . | Mouse model name . | Genetic approach and repeat number . | Behavioral phenotypes . | Prominent neuropathology . | Major advantages or special features . | References . |
|---|---|---|---|---|---|---|
| SBMA | AR113Q | Knock-in of human AR exon 1 containing 113 CAG repeats into mouse Ar locus | Weight loss, neuromuscular weakness (∼8 wk), testicular atrophy, reduced fertility, reduced survival (2–4 mo) | Myopathic and denervating changes in skeletal muscle, nuclear inclusions (NIs) in spinal neurons | Physiologically relevant expression of mutant protein. Pathology is androgen-dependent | Yu et al. (2006) |
| HD | CAG140 | Knock-in of human HTT exon 1 containing 140 CAG repeats into mouse Htt locus, homozygote | Hyperactivity followed by hypoactivity, motor deficits (∼4–6 mo), motor learning impairment, abnormal gait (>12 mo) | Selective striatal neuronal loss, reduced spine density of MSNs, cortical and striatal gliosis, NIs | Physiologically relevant expression of mutant protein. Slower progression is a more accurate representation of adult-onset HD progression | Menalled et al. (2003), Hickey et al. (2008) |
| YAC128 | Full-length human HTT transgene with 128 repeats (mostly pure CAG tract with some CAA interruptions), with all endogenous regulatory regions present | Motor learning deficits (∼2 mo), depression-like behavior, abnormal gait (∼8–12 mo), hyperactivity followed by hypoactivity | Selective striatal neuronal loss, cortical atrophy reduced brain weight, NIs, and reduced dopamine levels | Earlier and more robust phenotypes than the knock-in model. Exhibits psychiatric phenotypes too. Repeat number is stable | Slow et al. (2003), Van Raamsdonk et al. (2005) | |
| BAC-CAG HD | Full-length human HTT transgene encoding 131 glutamines, with an uninterrupted stretch of 120 CAGs. All endogenous regulatory regions present | Motor learning deficits (6 mo), hypoactivity, reduced grip strength, and sleep disruption | No overt brain atrophy. Loss of striatal MSNs synapses, NIs in striatum and cortex, astrogliosis, and microgliosis in the striatum | Somatic CAG instability in striatum, which correlates with behavioral impairment. The sequence also includes patient-associated SNPs | Gu et al. (2022) | |
| SCA1 | Atxn1154Q/2Q | Knock-in of 154 CAG repeats into mouse Atxn1 locus | Progressive motor deficits (onset ∼5 wk), cognitive deficits (∼7 wk), abnormal gait, weight loss, kyphosis, breathing deficits, and premature death (∼48 wk) | NIs, gradual PC pathology, hippocampal neuronal dysfunction, reduced brain weight, and ventricle enlargement | Physiologically relevant expression of mutant protein. Extensively characterized; closely reproduces SCA1 phenotypes | Watase et al. (2002), Jafar-Nejad et al. (2011) |
| SCA2 | Atxn2-CAG42 | Knock-in of 42 CAG repeats into mouse Atxn2 locus | Weight loss and late-onset cerebellar motor phenotypes (∼12 mo) | Cytoplasmic inclusions in PCs | Physiologically relevant expression of mutant protein | Damrath et al. (2012) |
| BAC-Q72 | Full-length human ATXN2 transgene with 72 CAG repeats, with all endogenous regulatory regions present | Motor deficits (onset ∼16 wk) and reduced body weight | Gradual PC pathology | Ubiquitous expression of mutant protein | Dansithong et al. (2015) | |
| SCA3 | YAC84Q (MJD84.2) | Full-length human ATXN3 transgene with 84 CAG repeats, with all endogenous regulatory regions present | Abnormal gait, late-onset motor deficits (∼30 wk), hypoactivity, kyphosis, and reduced body weight | NIs, neuronal loss in pontine and dentate nuclei, and gliosis | Expression of all isoforms of ATXN3. Resembles adult-onset SCA3 | Cemal et al. (2002) |
| SCA6 | Sca684Q/84Q | Knock-in of human exon 47 containing 84 CAG repeats into mouse Cacna1a locus, homozygote | Progressive motor impairment (onset at ∼7 mo) and abnormal gait | Cytoplasmic inclusions in PCs | Physiologically relevant expression of mutant protein. Resembles adult-onset disease | Watase et al. (2008) |
| SCA7 | Sca7266Q/5Q | Knock-in of 266 CAG repeats into mouse Atxn7 locus | Ptosis, visual impairment, ataxia, muscle wasting, kyphosis and tremors (onset ∼5 wk), hypokinesia, and premature death (4–5 mo) | NIs in brain and retina, cone-rod dystrophy, and reduced brain size | Physiologically relevant expression of mutant protein. Rapid progression, resembles infantile SCA7 | Yoo et al. (2003) |
| SCA17 | Germline-TBP 105Q | Knock-in of human exon 2 containing 105 CAG repeats into Tbp mouse locus, flanked by loxP sites under the control of Ella-Cre (germline) | Progressive motor deficits (onset ∼3 mo), ataxia, kyphosis, reduced body weight, premature death (∼5–10 mo) | PC degeneration, muscle degeneration, and TBP aggregation in muscle and brain | Proper spatiotemporal expression of mutant protein and relatively rapid progression | Huang et al. (2011), Huang et al. (2015) |
| DRPLA | Q129 | Full-length human DRPLA transgene with 129 CAG repeats, under the control of endogenous promoter | Myoclonus and ataxic gait (onset ∼3 wk), epileptic seizures (onset ∼9 wk), and premature death (by 16 wk) | NIs, reduced brain weight, and progressive cortical atrophy | Rapid onset of disease replicates juvenile-onset DRPLA | Sato et al. (2009) |
| Disease . | Mouse model name . | Genetic approach and repeat number . | Behavioral phenotypes . | Prominent neuropathology . | Major advantages or special features . | References . |
|---|---|---|---|---|---|---|
| SBMA | AR113Q | Knock-in of human AR exon 1 containing 113 CAG repeats into mouse Ar locus | Weight loss, neuromuscular weakness (∼8 wk), testicular atrophy, reduced fertility, reduced survival (2–4 mo) | Myopathic and denervating changes in skeletal muscle, nuclear inclusions (NIs) in spinal neurons | Physiologically relevant expression of mutant protein. Pathology is androgen-dependent | Yu et al. (2006) |
| HD | CAG140 | Knock-in of human HTT exon 1 containing 140 CAG repeats into mouse Htt locus, homozygote | Hyperactivity followed by hypoactivity, motor deficits (∼4–6 mo), motor learning impairment, abnormal gait (>12 mo) | Selective striatal neuronal loss, reduced spine density of MSNs, cortical and striatal gliosis, NIs | Physiologically relevant expression of mutant protein. Slower progression is a more accurate representation of adult-onset HD progression | Menalled et al. (2003), Hickey et al. (2008) |
| YAC128 | Full-length human HTT transgene with 128 repeats (mostly pure CAG tract with some CAA interruptions), with all endogenous regulatory regions present | Motor learning deficits (∼2 mo), depression-like behavior, abnormal gait (∼8–12 mo), hyperactivity followed by hypoactivity | Selective striatal neuronal loss, cortical atrophy reduced brain weight, NIs, and reduced dopamine levels | Earlier and more robust phenotypes than the knock-in model. Exhibits psychiatric phenotypes too. Repeat number is stable | Slow et al. (2003), Van Raamsdonk et al. (2005) | |
| BAC-CAG HD | Full-length human HTT transgene encoding 131 glutamines, with an uninterrupted stretch of 120 CAGs. All endogenous regulatory regions present | Motor learning deficits (6 mo), hypoactivity, reduced grip strength, and sleep disruption | No overt brain atrophy. Loss of striatal MSNs synapses, NIs in striatum and cortex, astrogliosis, and microgliosis in the striatum | Somatic CAG instability in striatum, which correlates with behavioral impairment. The sequence also includes patient-associated SNPs | Gu et al. (2022) | |
| SCA1 | Atxn1154Q/2Q | Knock-in of 154 CAG repeats into mouse Atxn1 locus | Progressive motor deficits (onset ∼5 wk), cognitive deficits (∼7 wk), abnormal gait, weight loss, kyphosis, breathing deficits, and premature death (∼48 wk) | NIs, gradual PC pathology, hippocampal neuronal dysfunction, reduced brain weight, and ventricle enlargement | Physiologically relevant expression of mutant protein. Extensively characterized; closely reproduces SCA1 phenotypes | Watase et al. (2002), Jafar-Nejad et al. (2011) |
| SCA2 | Atxn2-CAG42 | Knock-in of 42 CAG repeats into mouse Atxn2 locus | Weight loss and late-onset cerebellar motor phenotypes (∼12 mo) | Cytoplasmic inclusions in PCs | Physiologically relevant expression of mutant protein | Damrath et al. (2012) |
| BAC-Q72 | Full-length human ATXN2 transgene with 72 CAG repeats, with all endogenous regulatory regions present | Motor deficits (onset ∼16 wk) and reduced body weight | Gradual PC pathology | Ubiquitous expression of mutant protein | Dansithong et al. (2015) | |
| SCA3 | YAC84Q (MJD84.2) | Full-length human ATXN3 transgene with 84 CAG repeats, with all endogenous regulatory regions present | Abnormal gait, late-onset motor deficits (∼30 wk), hypoactivity, kyphosis, and reduced body weight | NIs, neuronal loss in pontine and dentate nuclei, and gliosis | Expression of all isoforms of ATXN3. Resembles adult-onset SCA3 | Cemal et al. (2002) |
| SCA6 | Sca684Q/84Q | Knock-in of human exon 47 containing 84 CAG repeats into mouse Cacna1a locus, homozygote | Progressive motor impairment (onset at ∼7 mo) and abnormal gait | Cytoplasmic inclusions in PCs | Physiologically relevant expression of mutant protein. Resembles adult-onset disease | Watase et al. (2008) |
| SCA7 | Sca7266Q/5Q | Knock-in of 266 CAG repeats into mouse Atxn7 locus | Ptosis, visual impairment, ataxia, muscle wasting, kyphosis and tremors (onset ∼5 wk), hypokinesia, and premature death (4–5 mo) | NIs in brain and retina, cone-rod dystrophy, and reduced brain size | Physiologically relevant expression of mutant protein. Rapid progression, resembles infantile SCA7 | Yoo et al. (2003) |
| SCA17 | Germline-TBP 105Q | Knock-in of human exon 2 containing 105 CAG repeats into Tbp mouse locus, flanked by loxP sites under the control of Ella-Cre (germline) | Progressive motor deficits (onset ∼3 mo), ataxia, kyphosis, reduced body weight, premature death (∼5–10 mo) | PC degeneration, muscle degeneration, and TBP aggregation in muscle and brain | Proper spatiotemporal expression of mutant protein and relatively rapid progression | Huang et al. (2011), Huang et al. (2015) |
| DRPLA | Q129 | Full-length human DRPLA transgene with 129 CAG repeats, under the control of endogenous promoter | Myoclonus and ataxic gait (onset ∼3 wk), epileptic seizures (onset ∼9 wk), and premature death (by 16 wk) | NIs, reduced brain weight, and progressive cortical atrophy | Rapid onset of disease replicates juvenile-onset DRPLA | Sato et al. (2009) |