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

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

Published in Volume 116, Issue 5

J Clin Invest. 2006; 116(5):1410–1424 doi:10.1172/JCI27607

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Figure 2

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

(A) Striatal neurons were transfected with 171-17Q-HA or 171-73Q-HA and HSJ1a, HSJ1b, or the corresponding empty vectors. Data (ANOVA, F_5,40 = 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, F_2,15 = 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, F_10,87 = 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.