Lentiviral gene delivery of GDNF into the striatum of R6/2 Huntington mice fails to attenuate behavioral and neuropathological changes

Popović, Natalija; Maingay, Matthew; Kirik, Deniz; Brundin, Patrik

doi:10.1016/j.expneurol.2004.12.009

Cited by 44 publications

(23 citation statements)

References 52 publications

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“…Several studies have shown that increased levels of glial cell line-derived neurotrophic factor (GDNF) can exert neuroprotective effects in acute HD animal models generated by intrastriatal injections of excitotoxins (for references see Popovic et al, 2005), making GDNF a good candidate for gene therapy in HD. Therefore, in order to evaluate if this neurotrophic factor was also protective in a chronic mouse model of HD, Popovic et al (2005) performed intrastriatal injections of lentiviral vectors containing the gdnf gene (LV-GDNF) in 5 week-old R6/2 mice.…”

Section: Genetic Manipulationsmentioning

confidence: 99%

“…Therefore, in order to evaluate if this neurotrophic factor was also protective in a chronic mouse model of HD, Popovic et al (2005) performed intrastriatal injections of lentiviral vectors containing the gdnf gene (LV-GDNF) in 5 week-old R6/2 mice. However, although a significant increase in the striatal expression of GDNF was detected in LV-GDNF-injected animals, no behavioral improvements were observed.…”

Section: Genetic Manipulationsmentioning

confidence: 99%

“…Furthermore, grafting of neural stem cells stably expressing GDNF and the firefly luciferase gene prevented the degeneration of striatal neurons and reduced the amphetamine-induced rotational behavior in an excitotoxic HD mouse model (Pineda et al, 2007). Nevertheless, the study by Popovic et al (2005) proves that overexpression of neurotrophic factors using lentiviral vectors is doable in the R6 mouse model, and therefore, the same techniques may be used to evaluate the effects of overexpression of other neurotrophic factors.…”

Section: Genetic Manipulationsmentioning

confidence: 99%

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The R6 lines of transgenic mice: A model for screening new therapies for Huntington's disease

Gil

Rego

2009

Brain Research Reviews

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Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by an expanded CAG repeat in the HD gene that results in cortical and striatal degeneration, and mutant huntingtin aggregation. Current treatments are unsatisfactory. R6 transgenic mice replicate many features of the human condition, show early onset of symptoms and fast disease progression, being one of the most used models for therapy screening. Here we review the therapies that have been tested in these mice: environmental enrichment, inhibition of histone deacetylation and methylation, inhibition of misfolding and oligomerization, transglutaminase inhibition, rescue of metabolic impairment, amelioration of the diabetic phenotype, use of antioxidants, inhibition of excitotoxicity, caspase inhibition, transplantation, genetic manipulations, and restoration of neurogenesis. Although many of these treatments were beneficial in R6 mice, they may not be as effective in HD patients, and thus the search for a combination of therapies that will rescue the human condition continues.

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Section: Genetic Manipulationsmentioning

confidence: 99%

Section: Genetic Manipulationsmentioning

confidence: 99%

Section: Genetic Manipulationsmentioning

confidence: 99%

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The R6 lines of transgenic mice: A model for screening new therapies for Huntington's disease

Gil

Rego

2009

Brain Research Reviews

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“…144 We recently showed that long-term lentiviral delivery of glial cell line-derived neurotrophic factor (GDNF) into the striatum of R6/2 mice, starting around the onset of motor symptoms, did not significantly affect Rotarod performances, open field behavior or neuropathologic changes. 145 There is growing evidence suggesting that BDNF synthesis and axonal transport are impaired in HD. 146 -149 Wild-type huntingtin up-regulates transcription of BDNF.…”

Section: Trophic Factor Delivery As An Optionmentioning

confidence: 99%

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

2005

Self Cite

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Summary:Huntington's disease (HD) is a genetic neurodegenerative disorder. Since identification of the disease-causing gene in 1993, a number of genetically modified animal models of HD have been generated. The first transgenic mouse models, R6/1 and R6/2 lines, were established 8 years ago. The R6/2 mice have been the best characterized and the most widely used model to study pathogenesis of HD and therapeutic interventions. In the present review, we especially focus on the characteristics of R6 transgenic mouse models and, in greater detail, describe the different therapeutic strategies that have been tested in these mice. We also, at the end, critically assess the relevance of the HD mouse models compared with the human disease and discuss how they can be best used in the future.

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“…While the molecular mechanisms by which an expanded polyglutamine tract leads to the selective loss of striatal neurons in HD patients is still to be fully elucidated, attention has been given to endogenously expressed neurotrophic factors known to play a critical role in the development and maintenance of the nervous system, including brain-derived neurotrophic factor (BDNF), [1][2][3][4] glial-derived neurotrophic factor 1,[5][6][7] and ciliary neurotrophic factor [8][9][10][11][12] to provide a broad approach to attenuate neurodegenerative processes.…”

Section: Introductionmentioning

confidence: 99%

AAV–BDNF mediated attenuation of quinolinic acid-induced neuropathology and motor function impairment

Henry

Connor

2008

Gene Ther

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Maintenance and plasticity of striatal neurons is dependant on brain-derived neurotrophic factor (BDNF), which is depleted in the Huntington's disease striatum due to reduced expression and disrupted corticostriatal transportation. In this study we demonstrate that overexpression of BDNF in the striatum attenuates motor impairment and reduces the extent of striatal damage following quinolinic acid lesioning. Transfer of the BDNF gene to striatal neurons using serotype 1/2 adenoassociated viral vectors enhanced BDNF protein levels in the striatum, but induced weight loss and seizure activity following long-term high-level expression. Lower concentration BDNF expression supported striatal neurons against excitotoxic insult, as demonstrated by enhanced krox-24 immunopositive neuron survival, reduction of striatal atrophy and maintenance of the patch/matrix organization. Additionally, BDNF expression attenuated motor impairment in the forelimb use cylinder test, sensorimotor neglect in the corridor food selection task and reversed apomorphine-induced rotational behaviour. Direct correlations were shown for the first time between BDNF-mediated attenuation of behavioural impairment and the integrity of the globus pallidus, seemingly independent from the severity of striatal lesioning. These results demonstrate that BDNF holds considerable therapeutic potential for alleviating both neuropathological and motor function deficits in the Huntington's disease brain, and the critical role of pallidal neurons in facilitating motor performance. Gene Therapy (2008) 15, 966-977;

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Lentiviral gene delivery of GDNF into the striatum of R6/2 Huntington mice fails to attenuate behavioral and neuropathological changes

Cited by 44 publications

References 52 publications

The R6 lines of transgenic mice: A model for screening new therapies for Huntington's disease

The R6 lines of transgenic mice: A model for screening new therapies for Huntington's disease

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

AAV–BDNF mediated attenuation of quinolinic acid-induced neuropathology and motor function impairment

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