The use of the R6 transgenic mouse models of Huntington’s disease in attempts to develop novel therapeutic strategies

Li, Jia Yi; Popović, Natalija; Brundin, Patrik

doi:10.1602/neurorx.2.3.447

Cited by 184 publications

(140 citation statements)

References 170 publications

Supporting

Mentioning

132

Contrasting

Unclassified

Order By: Relevance

“…Strain R6/2 is the product of strong expression of a transgene containing human mHTT exon 1 and its promoter (21). It has been widely used in the assessment of potential therapeutic interventions for HD (22,23). We found that D2GFP expression in the MSNs of R6/2 showed significant differences from the values for wild-type littermates at the earliest age we evaluated, 4.5-5 wk of age.…”

Section: D2gfp Loss Is Progressive In Both Fragment and Full-length Hdmentioning

confidence: 85%

Dysregulation of dopamine receptor D2 as a sensitive measure for Huntington disease pathology in model mice

Crook

Housman²

2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The ability to quantitatively evaluate the impact of a potential therapeutic intervention for Huntington disease (HD) in animal models for the disease is a critical step in the pathway to development of an effective therapy for this devastating neurodegenerative disorder. We report here an approach that combines a cell-based assay's quantitative accuracy and direct relationship to molecular processes with the ability to directly monitor effects in HD model mouse neurons. To accomplish this goal, we have developed an accurate quantitative reporter assay for a transcript known to be down-regulated as an early consequence of mutant huntingtin expression. This system uses mouse strains carrying a GFP reporter for the expression of the dopamine receptor D2, expressed in the medium spiny neurons of the basal ganglion. This receptor consistently demonstrates reduced expression in patients and murine models, and the FACS-based assay gives a highly accurate and quantitative readout of this pathology in mouse neurons expressing mutant huntingtin. For four genetic models and one viral model, a highly reproducible time course of loss of reporter expression is observed. This quantitative measure of HD pathology can be used to measure the effects of HD therapeutics in small cohorts with high confidence. We further demonstrate that the introduction of an shRNA against the huntingtin transgene by virus can improve this pathological status in medium spiny neurons transduced with the construct. We believe this system can be of great utility in the validation of effective therapeutic interventions for HD.neurodegeneration | polyglutamine | viral vectors | gene expression | neuroprotection I n the search for effective therapeutic interventions for neurodegenerative diseases such as ALS, Parkinson disease, Alzheimer's disease, and Huntington disease (HD), cell and animal models for all of these conditions have been developed. Whereas cell models allow higher throughput and lower cost, any therapeutic intervention initially evaluated in a cell-culture model must subsequently be assessed in an appropriate animal model system before clinical trials in humans can be considered. However, the inherent variance in quantitation of the behavioral or pathological readouts in animals has practical consequences, requiring large cohorts to detect all but the most overt benefits, which limits experimental throughput. We sought to develop and implement an approach to this problem that combines the quantitative accuracy and direct relationship to molecular processes of a cell-based assay with the medical relevance of evaluating endogenous neurons in the animal brain.In the present study, we have focused on HD. The uniform genetic etiology of HD, caused by a poly(CAG) expansion within exon 1 of huntingtin (HTT) (1), has provided an excellent starting point for the derivation of animal models for the disease. A number of similar animal models have been developed and characterized by behavioral and/or morphometric assessments of pathology (reviewed in...

show abstract

Section: D2gfp Loss Is Progressive In Both Fragment and Full-length Hdmentioning

confidence: 85%

Dysregulation of dopamine receptor D2 as a sensitive measure for Huntington disease pathology in model mice

Crook

Housman²

2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…1A, HDAC1 expression is elevated in the striatum of R6/2 mice, but not in extra-striatal tissues, which are relatively unaffected by neuropathology. It is known that neuropathology and behavioral deficits in R6/2 mice are not obvious at 6 weeks, but clearly discernible at 10 weeks of age (25). As shown in Fig.…”

Section: Hdac1 Promotesmentioning

confidence: 87%

“…R6/2 mice are transgenic for the first exon of the human huntingtin gene carrying about 120 CAG repeats. These mice exhibit a progressive neurological phenotype that mimics many features of human HD including selective striatal neuropathology, intracellular aggregates, reduced motor performance, and shortened lifespan (25). As shown in Fig.…”

Section: Hdac1 Promotesmentioning

confidence: 95%

Histone Deacetylase-1 (HDAC1) Is a Molecular Switch between Neuronal Survival and Death

Bardai

Price

Zaayman

et al. 2012

Journal of Biological Chemistry

122

111

View full text Add to dashboard Cite

Background:The role of HDAC1 in the regulation of neuronal survival is unresolved. Results: In cooperation with HDRP, HDAC1 promotes neuronal survival, but when it interacts with HDAC3, HDAC1 promotes neuronal death. Conclusion: HDAC1 can protect neurons or promote neuronal death depending on whether it interacts with HDRP or HDAC3. Significance: Our results provide insight into the role of HDAC1 in the regulation of neuronal survival.

show abstract

“…R6/2 mice express a 144 CAG repeat expansion within the first exon of the huntingtin gene, which yields a relatively severe disease phenotype. Untreated R6/2 mice develop rapidly progressive neurological impairment, and typically die between 13 and 15 weeks of age [140,141]. As in the rat, AdBDNF and AdNoggin treatment induced significant neuronal recruitment in both R6/2 mice and their wild-type controls [98].…”

Section: Induced Neuronal Addition As a Treatment For Huntington's DImentioning

confidence: 99%

Cellular Therapy and Induced Neuronal Replacement for Huntington's Disease

Benraiss

Goldman

2011

Neurotherapeutics

View full text Add to dashboard Cite

The use of the R6 transgenic mouse models of Huntington’s disease in attempts to develop novel therapeutic strategies

Cited by 184 publications

References 170 publications

Dysregulation of dopamine receptor D2 as a sensitive measure for Huntington disease pathology in model mice

Dysregulation of dopamine receptor D2 as a sensitive measure for Huntington disease pathology in model mice

Histone Deacetylase-1 (HDAC1) Is a Molecular Switch between Neuronal Survival and Death

Cellular Therapy and Induced Neuronal Replacement for Huntington's Disease

Contact Info

Product

Resources

About