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 4

HSJ1b increases BDNF processing from the Golgi to the cytoplasm.

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HSJ1b increases BDNF processing from the Golgi to the cytoplasm. (A) BDN...
(A) BDNF, clathrin, and HSJ1b were present in the same cellular compartments: small vesicle fraction (P3) and CCV fraction (p). (B) HSJ1b partially colocalized with the Golgi apparatus. (C) HSJ1b enhanced colocalization between BDNF and clathrin in the Golgi region, whereas RNAi-HSJ1 disrupted it. Scale bars: 10 μm. (D) Quantification (ANOVA, F3,64 = 7.71; P = 0.0002) revealed that expression of HSJ1b significantly increased the amount of BDNF vesicles that were clathrin positive compared with control cells (post-hoc Fisher’s test, P = 0.032), while pSUPER-RNAi-HSJ1 significantly decreased it (post-hoc Fisher’s test, P = 0.019). Overexpression of HSJ1a had no effect (NS). (E) Scheme showing the measurement of BDNF in the Golgi area (left) and in the cytoplasm (sorted vesicles, right). (F) Quantification (ANOVA, F3,67 = 2,92; P = 0.04) revealed that lowering HSJ1b by interference significantly decreased BDNF content in the Golgi area (post-hoc Fisher’s test, P = 0.005). There was no difference between cells expressing HSJ1b or HSJ1a compared with control conditions (NS). (G) Quantification (ANOVA, F3,47 = 5,84; P = 0.0018) revealed that HSJ1b increased the amount of BDNF vesicles in the cytoplasm in comparison to control cells (post-hoc Fisher’s test, P = 0.048), whereas pSUPER-RNAi-HSJ1 decreased it (post-hoc Fisher’s test, P = 0.038). The difference was not significant in HSJ1a-overexpressing cells (NS). *P < 0.05, **P < 0.01.