title: 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.affiliation: Institut Curie, CNRS UMR 146, Orsay, France.
authors.forename: Maria
authors.initials: M
authors.lastname: Borrell-Pagès
authors.forename: Josep M
authors.initials: JM
authors.lastname: Canals
authors.forename: Fabrice P
authors.initials: FP
authors.lastname: Cordelières
authors.forename: J Alex
authors.initials: JA
authors.lastname: Parker
authors.forename: José R
authors.initials: JR
authors.lastname: Pineda
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Grange
authors.forename: Elzbieta A
authors.initials: EA
authors.lastname: Bryson
authors.forename: Martine
authors.initials: M
authors.lastname: Guillermier
authors.forename: Etienne
authors.initials: E
authors.lastname: Hirsch
authors.forename: Philippe
authors.initials: P
authors.lastname: Hantraye
authors.forename: Michael E
authors.initials: ME
authors.lastname: Cheetham
authors.forename: Christian
authors.initials: C
authors.lastname: Néri
authors.forename: Jordi
authors.initials: J
authors.lastname: Alberch
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Brouillet
authors.forename: Frédéric
authors.initials: F
authors.lastname: Saudou
authors.forename: Sandrine
authors.initials: S
authors.lastname: Humbert
mesh_terms: D000368:Aged; D000818:Animals; D001921:Brain / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis*; D017173:Caenorhabditis elegans; D003538:Cystamine / Q000737:chemistry* / Q000378:metabolism*; D003543:Cysteamine / Q000737:chemistry*; D050956:HSP40 Heat-Shock Proteins / Q000502:physiology*; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism*; D008251:Macaca; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D018832:Molecular Chaperones / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011503:Transglutaminases / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C121958:DNAJB2 protein, human; D050956:HSP40 Heat-Shock Proteins; D018832:Molecular Chaperones; D018696:Neuroprotective Agents; D003543:Cysteamine; D011503:Transglutaminases; D003538:Cystamine