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 2

HSJ1 proteins and polyQ-huntingtin–induced toxicity and dysfunction.

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HSJ1 proteins and polyQ-huntingtin–induced toxicity and dysfunction. (A)...
(A) Striatal neurons were transfected with 171-17Q-HA or 171-73Q-HA and HSJ1a, HSJ1b, or the corresponding empty vectors. Data (ANOVA, F5,40 = 6.89; P < 0.0001) demonstrated that cell death was significantly increased by 171-73Q-HA construct (post-hoc Fisher’s test, P < 0.01) and blocked by cotransfection with HSJ1a (post-hoc Fisher’s test, P = 0.0043) or HSJ1b (post-hoc Fisher’s test, P < 0.0001). (B) Cell extracts prepared from 171-73Q-HA–transfected HEK 293T cells were analyzed by immunoblotting using an anti-HA antibody. (C) Striatal neurons were transfected with 171-17Q-HA or 171-73Q-HA together with HSJ1a, HSJ1b, or the corresponding empty vectors. Data (ANOVA, F2,15 = 4.43; P = 0.031) revealed a statistically significant decrease in the percentage of neurons with intranuclear inclusions in the presence of HSJ1a (post-hoc Fisher’s test, P = 0.0094) but not of HSJ1b (NS). (D) Data (ANOVA, F10,87 = 23.44; P < 0.0001) revealed a statistically significant decrease in mechanosensation of touch receptor neurons in the tail of animals expressing the exon 1–128Q-GFP construct compared with neurons expressing exon 1–19Q-GFP (Student’s t test, t[16] = 16.12; P < 0.0001). Loss of touch response mediated by exon 1–128Q-GFP was inhibited by expression of HSJ1b (Student’s t test, t[16] = 9.01; P < 0.0001). (E) Morphometric analysis revealed no change in the aggregation of fusion proteins in the cell bodies of neurons from HSJ1b-expressing animals (Student’s t test, t[198] = 1.22; NS). **P < 0.01, #P < 0.001.