Symptomatic Treatment of Huntington Disease

Adam, Octavian R.; Jankovic, Joseph

doi:10.1016/j.nurt.2008.01.008

Cited by 103 publications

(79 citation statements)

References 112 publications

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“…Presently, there is no efficient treatment for HD patients. 38,39 A large number of clinical trials, testing pharmacological approaches, have so far produced discouraging results. 39,40 Neuroprotective strategies using several growth factors have also been proposed for HD.…”

Section: Discussionmentioning

confidence: 99%

BDNF regulation under GFAP promoter provides engineered astrocytes as a new approach for long-term protection in Huntington's disease

et al. 2010

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Brain-derived neurotrophic factor (BDNF) is the main candidate for neuroprotective therapeutic strategies for Huntington's disease. However, the administration system and the control over the dosage are still important problems to be solved. Here we generated transgenic mice overexpressing BDNF under the promoter of the glial fibrillary acidic protein (GFAP) (pGFAP-BDNF mice). These mice are viable and have a normal phenotype. However, intrastriatal administration of quinolinate increased the number of reactive astrocytes and enhanced the release of BDNF in pGFAP-BDNF mice compared with wild-type mice. Coincidentally, pGFAP-BDNF mice are more resistant to quinolinate than wild-type mice, suggesting a protective effect of astrocyte-derived BDNF. To verify this, we next cultured astrocytes from pGFAP-BDNF and wild-type mice for grafting. Wild-type and pGFAP-BDNF-derived astrocytes behave similarly in nonlesioned mice. However, pGFAP-BDNF-derived astrocytes showed higher levels of BDNF and larger neuroprotective effects than the wild-type ones when quinolinate was injected 30 days after grafting. Interestingly, mice grafted with pGFAP-BDNF astrocytes showed important and sustained behavioral improvements over time after quinolinate administration as compared with mice grafted with wild-type astrocytes. These findings show that astrocytes engineered to release BDNF can constitute a therapeutic approach for Huntington's disease.

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Section: Discussionmentioning

confidence: 99%

BDNF regulation under GFAP promoter provides engineered astrocytes as a new approach for long-term protection in Huntington's disease

et al. 2010

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“…Chorea Several reviews have summarized the symptomatic treatment of chorea associated with HD [49][50][51][52][53][54][55][56][57][58][59][60][61]. Overall, there is not enough evidence available to guide long-term symptomatic treatment in HD, and double-blind and long-term studies assessing various treatment strategies in HD are needed [55].…”

Section: Pharmacological Treatment Optionsmentioning

confidence: 99%

Treatment of Huntington's Disease

2014

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“…Currently, there is no cure for HD, with drugs only available for symptomatic treatment. 45 Canonical ER stress response and the UPR have been implicated in a wide variety of disorders, including diabetes, cancer, inflammatory diseases and neurodegeneration. 6 Although an enhanced activation of the survival arms of the UPR is observed in cancers, the apoptotic pathways are more prevalent in several neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 99%

The transrepression arm of glucocorticoid receptor signaling is protective in mutant huntingtin-mediated neurodegeneration

et al. 2015

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The unfolded protein response (UPR) occurs following the accumulation of unfolded proteins in the endoplasmic reticulum (ER) and orchestrates an intricate balance between its prosurvival and apoptotic arms to restore cellular homeostasis and integrity. However, in certain neurodegenerative diseases, the apoptotic arm of the UPR is enhanced, resulting in excessive neuronal cell death and disease progression, both of which can be overcome by modulating the UPR. Here, we describe a novel crosstalk between glucocorticoid receptor signaling and the apoptotic arm of the UPR, thus highlighting the potential of glucocorticoid therapy in treating neurodegenerative diseases. Several glucocorticoids, but not mineralocorticoids, selectively antagonize ER stress-induced apoptosis in a manner that is downstream of and/or independent of the conventional UPR pathways. Using GRT10, a novel selective pharmacological modulator of glucocorticoid signaling, we describe the importance of the transrepression arm of the glucocorticoid signaling pathway in protection against ER stress-induced apoptosis. Furthermore, we also observe the protective effects of glucocorticoids in vivo in a Drosophila model of Huntington's disease (HD), wherein treatment with different glucocorticoids diminished rhabdomere loss and conferred neuroprotection. Finally, we find that growth differentiation factor 15 has an important role downstream of glucocorticoid signaling in antagonizing ER stress-induced apoptosis in cells, as well as in preventing HD-mediated neurodegeneration in flies. Thus, our studies demonstrate that this novel crosstalk has the potential to be effectively exploited in alleviating several neurodegenerative disorders.

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Symptomatic Treatment of Huntington Disease

Cited by 103 publications

References 112 publications

BDNF regulation under GFAP promoter provides engineered astrocytes as a new approach for long-term protection in Huntington's disease

BDNF regulation under GFAP promoter provides engineered astrocytes as a new approach for long-term protection in Huntington's disease

Treatment of Huntington's Disease

The transrepression arm of glucocorticoid receptor signaling is protective in mutant huntingtin-mediated neurodegeneration

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