Cystamine and cysteamine increase brain levels of BDNF in Huntington disease via HSJ1b and transglutaminase
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
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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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 5

Cystamine and TGase 2 regulate BDNF secretion.

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Cystamine and TGase 2 regulate BDNF secretion. (A) Cystamine treatment (...
(A) Cystamine treatment (100 μM, 30 minutes) of BDNF-GFP–transfected cells decreased colocalization between BDNF and GM130. BFA dispersed BDNF vesicles and GM130 with or without cystamine. (B) Quantification (ANOVA, F2,46 = 7.10; P = 0.0021) revealed that cystamine significantly decreased BDNF in the Golgi area compared with control cells at 30 minutes (post-hoc Fisher’s test, P = 0.011) and 2 hours (post-hoc Fisher’s test, P = 0.0007). (C) Data (ANOVA, F2,46 = 4.83; P = 0.0125) revealed that cystamine treatment significantly increased BDNF content in cytoplasmic vesicles compared with control cells at 30 minutes (post-hoc Fisher’s test, P = 0.021) and 2 hours (post-hoc Fisher’s test; P = 0.0049). (D) Data (ANOVA, F3,32 = 45.6; P < 0.0001) revealed that BFA significantly reduced BDNF release in control and cystamine-treated cells (post-hoc Fisher’s test, P < 0.0001). Cystamine had an effect on control (post-hoc Fisher’s test, P < 0.006) but not on BFA-treated cells (NS). (E) TGase 2 colocalization with HSJ1b at the Golgi (GMAP-210) was disrupted in pSUPER-RNAi-HSJ1–transfected cells. (F) TGase overexpression induced a decrease in cytoplasmic BDNF-containing vesicles. Scale bars: 10 μm. (G) TGase 2 did not modify BDNF content in the Golgi area compared with control cells (Student’s t test, t[13] = 0.4; NS). (H) TGase 2 induced a statistically significant decrease in cytoplasmic BDNF vesicles compared with control cells (Student’s t test, t[13] = 3.4; P = 0.0051). *P < 0.05, **P < 0.01, and #P < 0.001.