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

1. J Clin Invest. 2006 May;116(5):1410-24. Epub 2006 Apr 6.

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

Borrell-Pagès M(1), Canals JM, Cordelières FP, Parker JA, Pineda JR, Grange G,
Bryson EA, Guillermier M, Hirsch E, Hantraye P, Cheetham ME, Néri C, Alberch J,
Brouillet E, Saudou F, Humbert S.

Author information:
(1)Institut Curie, CNRS UMR 146, Orsay, France.

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.

DOI: 10.1172/JCI27607
PMCID: PMC1430359
PMID: 16604191 [Indexed for MEDLINE]

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