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


Autoria(s): Borrell Pagès, Maria; Canals i Coll, Josep M.; Cordelières, Fabrice P.; Parker, J. Alex; Pineda Martí, José Ramón; Grange, Ghislaine; Bryson, Elzbieta A.; Guillermier, Martine; Hirsch, Etienne; Hantraye, Philippe; Cheetham, Michael E.; Néri, Christian; Alberch i Vié, Jordi; Brouillet, Emmanuel; Saudou, Frédéric; Humbert, Sandrine
Contribuinte(s)

Universitat de Barcelona

Data(s)

04/05/2010

Resumo

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.

Identificador

http://hdl.handle.net/2445/8314

Idioma(s)

eng

Publicador

American Society for Clinical Investigation

Direitos

(c) The American Society for Clinical Investigation, 2006

info:eu-repo/semantics/openAccess

Palavras-Chave #Corea de Huntington #Degeneració del sistema nerviós #Quimioteràpia #Huntington's chorea #Neurodegenerative Diseases #Chemotherapy
Tipo

info:eu-repo/semantics/article