Evaluation of the benzothiazole aggregation inhibitors riluzole and PGL-135 as therapeutics for Huntington's disease

Hockly, Emma; Tse, Jamie; Barker, Amy L.; Moolman, Donna L.; Beunard, Jean‐Luc; Revington, A P; Holt, Kim; Sunshine, Sunny; Moffitt, H. Lee; Sathasivam, Kirupa; Woodman, Benjamin; Wanker, Erich E.; Lowden, Philip A.S; Bates, Gillian P.

doi:10.1016/j.nbd.2005.07.007

Cited by 70 publications

(77 citation statements)

References 27 publications

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“…First, we evaluated the capacity of known inhibitors of the polyQ aggregation process to suppress Q102-GFP aggregation in this vertebrate system. PGL-135 and Congo red (16,29) reduced Q102-GFP aggregation in zebrafish, as judged by the filter trap assay (Fig. 6A).…”

Section: Polyq-expanded Htt Is Deposited Into Inclusions Of Sds-insolmentioning

confidence: 88%

“…Instead, soluble intermediates in the aggregation pathway are likely to be the key toxic species, giving rise to neurodegeneration through various mechanisms including inactivation of essential transcription factors and inhibition of the ubiquitin proteasome system (12,13). Much attention has therefore been focused on identifying means to disrupt or alter the polyQ aggregation pathway (14), and several compounds with antiaggregation activity have been identified in vitro and in cellbased assays (15,16).…”

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confidence: 99%

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Identification of Anti-prion Compounds as Efficient Inhibitors of Polyglutamine Protein Aggregation in a Zebrafish Model

Schiffer

Broadley

Hirschberger

et al. 2007

Journal of Biological Chemistry

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Section: Polyq-expanded Htt Is Deposited Into Inclusions Of Sds-insolmentioning

confidence: 88%

mentioning

confidence: 99%

Identification of Anti-prion Compounds as Efficient Inhibitors of Polyglutamine Protein Aggregation in a Zebrafish Model

Schiffer

Broadley

Hirschberger

et al. 2007

Journal of Biological Chemistry

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“…HeLa cells were pretreated with Pgl-135, a benzothioazole known to reduce aggregation of httEx1 (32). Given that Pgl-135 dose-dependently suppressed httEx1Q97 IB-and SDS-insoluble protein leveling off at 50 M (supplemental Fig.…”

Section: Inhibition Of Poly(q) Aggregation Suppresses Ros Production-mentioning

confidence: 99%

In Vitro and in Vivo Aggregation of a Fragment of Huntingtin Protein Directly Causes Free Radical Production

Hands

Sajjad²,

Newton

et al. 2011

Journal of Biological Chemistry

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Background: Neurodegenerative diseases are associated with intracellular protein aggregation and free radical damage. Results: Protein aggregation of polyglutamine-containing proteins directly causes free radical production in vitro and within cells. Conclusion: Protein aggregation during polyglutamine diseases could be targeted to prevent oxidative stress. Significance: Intracellular protein aggregation during chronic neurodegeneration is closely linked to abnormal production of free radicals.

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“…Nevertheless, in a more recent study, oral administration of riluzole was inefficient at the level of aggregation and did not improve the R6/2 phenotype (body weight loss, rotarod performance, grip strength, and open field activity) (Hockly et al, 2006). Despite these discrepancies, clinical trials of riluzole in HD patients have been performed (Rosas et al, 1999;Seppi et al, 2001;Huntington Study Group, 2003;Landwehrmeyer et al, 2007).…”

Section: Inhibition Of Excitotoxicitymentioning

confidence: 99%

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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Evaluation of the benzothiazole aggregation inhibitors riluzole and PGL-135 as therapeutics for Huntington's disease

Cited by 70 publications

References 27 publications

Identification of Anti-prion Compounds as Efficient Inhibitors of Polyglutamine Protein Aggregation in a Zebrafish Model

Identification of Anti-prion Compounds as Efficient Inhibitors of Polyglutamine Protein Aggregation in a Zebrafish Model

In Vitro and in Vivo Aggregation of a Fragment of Huntingtin Protein Directly Causes Free Radical Production

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

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