Methylene Blue Modulates Huntingtin Aggregation Intermediates and is Protective in Huntington's Disease Models

Authors

Emily M. Sontag, Marquette UniversityFollow
Gregor P. Lotz, University of California - San Francisco
Namita Agrawal, University of California, Irvine
Andrew Tran, University of California, Irvine
Rebecca Aron, University of California - San Francisco
Guocheng Yang, University of California - San FranciscoFollow
Mihaela Necula, University of California, Irvine
Alice Lau, University of California, Irvine
Steven Finkbeiner, University of California, San FranciscoFollow
Charles G. Glabe, University of California - Irvine
J. Lawrence Marsh, University of California, Irvine
Paul J. Muchowski, University of California - San Francisco
Leslie M. Thompson, University of California, Irvine

Document Type

Article

Publication Date

8-8-2012

Publisher

Society of Neuroscience

Source Publication

Journal of Neuroscience

Source ISSN

0270-6474

Original Item ID

DOI: 10.1523/jneurosci.0895-12.2012

Abstract

Huntington's disease (HD) is a devastating neurodegenerative disorder with no disease-modifying treatments available. The disease is caused by expansion of a CAG trinucleotide repeat and manifests with progressive motor abnormalities, psychiatric symptoms, and cognitive decline. Expression of an expanded polyglutamine repeat within the Huntingtin (Htt) protein impacts numerous cellular processes, including protein folding and clearance. A hallmark of the disease is the progressive formation of inclusions that represent the culmination of a complex aggregation process. Methylene blue (MB), has been shown to modulate aggregation of amyloidogenic disease proteins. We investigated whether MB could impact mutant Htt-mediated aggregation and neurotoxicity. MB inhibited recombinant protein aggregation in vitro, even when added to preformed oligomers and fibrils. MB also decreased oligomer number and size and decreased accumulation of insoluble mutant Htt in cells. In functional assays, MB increased survival of primary cortical neurons transduced with mutant Htt, reduced neurodegeneration and aggregation in a Drosophila melanogaster model of HD, and reduced disease phenotypes in R6/2 HD modeled mice. Furthermore, MB treatment also promoted an increase in levels of BDNF RNA and protein in vivo. Thus, MB, which is well tolerated and used in humans, has therapeutic potential for HD.

Comments

Published version. Journal of Neuroscience, Vol. 32, No. 32 (August 8, 2012): 11109-11119. DOI. © 2012 Society for Neuroscience. Used with permission.

Recommended Citation

Sontag, Emily M.; Lotz, Gregor P.; Agrawal, Namita; Tran, Andrew; Aron, Rebecca; Yang, Guocheng; Necula, Mihaela; Lau, Alice; Finkbeiner, Steven; Glabe, Charles G.; Marsh, J. Lawrence; Muchowski, Paul J.; and Thompson, Leslie M., "Methylene Blue Modulates Huntingtin Aggregation Intermediates and is Protective in Huntington's Disease Models" (2012). Biological Sciences Faculty Research and Publications. 907.
https://epublications.marquette.edu/bio_fac/907