Cystamine and cysteamine increase brain levels of BDNF in Huntington disease via HSJ1b and transglutaminase
Maria Borrell-Pagès, … , Frédéric Saudou, Sandrine Humbert
Maria Borrell-Pagès, … , Frédéric Saudou, Sandrine Humbert
Published May 1, 2006
Citation Information: J Clin Invest. 2006;116(5):1410-1424. https://doi.org/10.1172/JCI27607.
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Research Article Neuroscience

Cystamine and cysteamine increase brain levels of BDNF in Huntington disease via HSJ1b and transglutaminase

Abstract

There is no treatment for the neurodegenerative disorder Huntington disease (HD). Cystamine is a candidate drug; however, the mechanisms by which it operates remain unclear. We show here that cystamine increases levels of the heat shock DnaJ-containing protein 1b (HSJ1b) that are low in HD patients. HSJ1b inhibits polyQ-huntingtin–induced death of striatal neurons and neuronal dysfunction in Caenorhabditis elegans. This neuroprotective effect involves stimulation of the secretory pathway through formation of clathrin-coated vesicles containing brain-derived neurotrophic factor (BDNF). Cystamine increases BDNF secretion from the Golgi region that is blocked by reducing HSJ1b levels or by overexpressing transglutaminase. We demonstrate that cysteamine, the FDA-approved reduced form of cystamine, is neuroprotective in HD mice by increasing BDNF levels in brain. Finally, cysteamine increases serum levels of BDNF in mouse and primate models of HD. Therefore, cysteamine is a potential treatment for HD, and serum BDNF levels can be used as a biomarker for drug efficacy.

Authors

Maria Borrell-Pagès, Josep M. Canals, Fabrice P. Cordelières, J. Alex Parker, José R. Pineda, Ghislaine Grange, Elzbieta A. Bryson, Martine Guillermier, Etienne Hirsch, Philippe Hantraye, Michael E. Cheetham, Christian Néri, Jordi Alberch, Emmanuel Brouillet, Frédéric Saudou, Sandrine Humbert

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Figure 3

HSJ1b and cystamine increase BDNF release.

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HSJ1b and cystamine increase BDNF release. (A) Neuronal cells were trans...
(A) Neuronal cells were transfected with BDNF, HSJ1a, HSJ1b, or the corresponding empty vectors. Forty-eight hours after transfection, cells were washed with PBS and incubated for 30 minutes with DMEM, and supernatants (super.) were collected. Data (ANOVA, F2,31 = 9.17; P = 0.0007) revealed that HSJ1b (post-hoc Fisher’s test, P = 0.0002), but not HSJ1a (NS), induced a statistically significant increase in BDNF release. (B) Data (ANOVA, F3,39 = 323.66; P < 0.0001) revealed a statistically significant increase in BDNF content in the supernatant of 100 μM cystamine-treated cells at 24, 48, and 72 hours (post-hoc Fisher’s test, P < 0.0001). (C) Cells transfected with BDNF and treated with cystamine were analyzed by immunoblotting with anti-BDNF and anti–β-actin antibodies. (D) Data (ANOVA, F3,29 = 26.01; P < 0.0001) revealed a statistically significant decrease in HSJ1 transcripts in cells transfected with siRNA-HSJ1 compared with control cells with or without cystamine treatment (post-hoc Fisher’s test, P < 0.0001). Cystamine increased HSJ1 transcripts in control conditions (post-hoc Fisher’s test, P = 0.002) but not in the presence of siRNA-HSJ1 (NS). (E) Cystamine did not increase BDNF release when HSJ1b levels were lowered by RNAi-HSJ1 (ANOVA, F3,19 = 7.59; P = 0.0016). Cells were cotransfected with BDNF and pSUPER-RNAi-HSJ1 and treated with cystamine 48 hours after transfection. There was a significant increase in BDNF release in cystamine-treated cells compared with control cells (post-hoc Fisher’s test, P = 0.0005). **P < 0.01, #P < 0.001.