title: A critical window of CAG repeat-length correlates with phenotype severity in the R6/2 mouse model of Huntington's disease.
abstract: The R6/2 mouse is the most frequently used model for experimental and preclinical drug trials in Huntington's disease (HD). When the R6/2 mouse was first developed, it carried exon 1 of the huntingtin gene with ~150 cytosine-adenine-guanine (CAG) repeats. The model presented with a rapid and aggressive phenotype that shared many features with the human condition and was particularly similar to juvenile HD. However, instability in the CAG repeat length due to different breeding practices has led to both decreases and increases in average CAG repeat lengths among colonies. Given the inverse relationship in human HD between CAG repeat length and age at onset and to a degree, the direct relationship with severity of disease, we have investigated the effect of altered CAG repeat length. Four lines, carrying ~110, ~160, ~210, and ~310 CAG repeats, were examined using a battery of tests designed to assess the basic R6/2 phenotype. These included electrophysiological properties of striatal medium-sized spiny neurons, motor activity, inclusion formation, and protein expression. The results showed an unpredicted, inverted "U-shaped" relationship between CAG repeat length and phenotype; increasing the CAG repeat length from 110 to 160 exacerbated the R6/2 phenotype, whereas further increases to 210 and 310 CAG repeats greatly ameliorated the phenotype. These findings demonstrate that the expected relationship between CAG repeat length and disease severity observed in humans is lost in the R6/2 mouse model and highlight the importance of CAG repeat-length determination in preclinical drug trials that use this model.
authors.affiliation: Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles, California 90095, USA.
authors.forename: Damian M
authors.initials: DM
authors.lastname: Cummings
authors.forename: Yasaman
authors.initials: Y
authors.lastname: Alaghband
authors.forename: Miriam A
authors.initials: MA
authors.lastname: Hickey
authors.forename: Prasad R
authors.initials: PR
authors.lastname: Joshi
authors.forename: S Candice
authors.initials: SC
authors.lastname: Hong
authors.forename: Chunni
authors.initials: C
authors.lastname: Zhu
authors.forename: Timothy K
authors.initials: TK
authors.lastname: Ando
authors.forename: Véronique M
authors.initials: VM
authors.lastname: André
authors.forename: Carlos
authors.initials: C
authors.lastname: Cepeda
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Watson
authors.forename: Michael S
authors.initials: MS
authors.lastname: Levine
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001835:Body Weight / Q000235:genetics; D003342:Corpus Striatum / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005106:Exploratory Behavior / Q000502:physiology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D053580:Muscle Strength / Q000235:genetics; D016202:N-Methylaspartate / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000473:pathology / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010641:Phenotype; D045442:Rotarod Performance Test; D012640:Seizures / Q000209:etiology / Q000235:genetics; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: D018690:Excitatory Amino Acid Agonists; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D016202:N-Methylaspartate
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