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

J Clin Invest. 2006 May;116(5):1410-24. doi: 10.1172/JCI27607. Epub 2006 Apr 6.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Brain / metabolism*
  • Brain-Derived Neurotrophic Factor / biosynthesis*
  • Caenorhabditis elegans
  • Cystamine / chemistry*
  • Cystamine / metabolism*
  • Cysteamine / chemistry*
  • HSP40 Heat-Shock Proteins / physiology*
  • Humans
  • Huntington Disease / metabolism*
  • Macaca
  • Mice
  • Mice, Transgenic
  • Middle Aged
  • Molecular Chaperones / physiology*
  • Neuroprotective Agents / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Transglutaminases / metabolism*


  • Brain-Derived Neurotrophic Factor
  • DNAJB2 protein, human
  • HSP40 Heat-Shock Proteins
  • Molecular Chaperones
  • Neuroprotective Agents
  • Cysteamine
  • Transglutaminases
  • Cystamine