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A critical window of CAG repeat-length correlates with phenotype severity in the R6/2 mouse model of Huntington's disease.
- Source :
-
Journal of neurophysiology [J Neurophysiol] 2012 Jan; Vol. 107 (2), pp. 677-91. Date of Electronic Publication: 2011 Nov 09. - Publication Year :
- 2012
-
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.
- Subjects :
- Analysis of Variance
Animals
Body Weight genetics
Corpus Striatum pathology
Corpus Striatum physiopathology
Disease Models, Animal
Disease Progression
Excitatory Amino Acid Agonists pharmacology
Excitatory Postsynaptic Potentials physiology
Exploratory Behavior physiology
Genotype
Humans
Huntingtin Protein
Huntington Disease metabolism
Huntington Disease pathology
In Vitro Techniques
Inhibitory Postsynaptic Potentials drug effects
Inhibitory Postsynaptic Potentials genetics
Mice
Mice, Inbred C57BL
Mice, Transgenic
Motor Activity genetics
Muscle Strength genetics
N-Methylaspartate pharmacology
Nerve Tissue Proteins genetics
Nerve Tissue Proteins metabolism
Neurons pathology
Neurons physiology
Nuclear Proteins genetics
Nuclear Proteins metabolism
Patch-Clamp Techniques
Rotarod Performance Test
Seizures etiology
Seizures genetics
Genetic Predisposition to Disease genetics
Huntington Disease genetics
Huntington Disease physiopathology
Phenotype
Trinucleotide Repeat Expansion genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1522-1598
- Volume :
- 107
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Journal of neurophysiology
- Publication Type :
- Academic Journal
- Accession number :
- 22072510
- Full Text :
- https://doi.org/10.1152/jn.00762.2011