Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • Hypoxia-inducible factors in disease pathophysiology and therapeutics (Oct 2020)
    • Latency in Infectious Disease (Jul 2020)
    • Immunotherapy in Hematological Cancers (Apr 2020)
    • Big Data's Future in Medicine (Feb 2020)
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • View all review series ...
  • Viewpoint
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
Cystamine and cysteamine increase brain levels of BDNF in Huntington disease via HSJ1b and transglutaminase
Maria Borrell-Pagès, … , Frédéric Saudou, Sandrine Humbert
Maria Borrell-Pagès, … , Frédéric Saudou, Sandrine Humbert
Published May 1, 2006
Citation Information: J Clin Invest. 2006;116(5):1410-1424. https://doi.org/10.1172/JCI27607.
View: Text | PDF
Research Article Neuroscience

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

  • Text
  • PDF
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

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

×

Figure 1

Cystamine increases HSJ1 transcript levels in neuronal cells, while HSJ1b is decreased in postmortem brain extracts from HD patients.

Options: View larger image (or click on image) Download as PowerPoint
Cystamine increases HSJ1 transcript levels in neuronal cells, while HSJ1...
(A) Data revealed a statistically significant increase in HSJ1 transcripts induced by cystamine treatment in comparison to control at 24 hours (Student’s t test, t[21] = 5.77; P < 0.0001) and at 48 hours (Student’s t test, t[10] = 9.88; P < 0.0001). (B) Protein extracts prepared from 1 control human cortical postmortem sample and from HEK 293T cells transfected with HSJ1a or HSJ1b were immunoblotted with an anti-HSJ1 antibody. The major brain isoform of HSJ1 proteins was the HSJ1b isoform. (C–E) Protein extracts were prepared from whole striatum (C), putamen (D), and caudate nucleus (E) of control (CT) and HD individuals and analyzed as in B. Immunoblotting with an anti–β-actin antibody was used as a control. (F) Quantification of the Western blots presented in C–E showed a statistically significant decrease in the protein level of HSJ1b in HD samples (n = 12) compared with control samples (n = 15) (Student’s t test, t[25] = 2.33; P = 0.028). *P < 0.05, #P < 0.0001.
Follow JCI:
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts