Table 2. Some of the most accurate mouse... | Rockefeller University Press

Table 2.

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	Atxn1^154Q/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)
SCA2	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	Sca6^84Q/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	Sca7^266Q/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	Atxn1^154Q/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)
SCA2	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	Sca6^84Q/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	Sca7^266Q/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)