title: Methylene blue modulates huntingtin aggregation intermediates and is protective in Huntington's disease models.
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.
authors.affiliation: Department of Biological Chemistry, Psychiatry and Human Behavior, University of California, Irvine, California 92697, USA.
authors.forename: Emily Mitchell
authors.initials: EM
authors.lastname: Sontag
authors.forename: Gregor P
authors.initials: GP
authors.lastname: Lotz
authors.forename: Namita
authors.initials: N
authors.lastname: Agrawal
authors.forename: Andrew
authors.initials: A
authors.lastname: Tran
authors.forename: Rebecca
authors.initials: R
authors.lastname: Aron
authors.forename: Guocheng
authors.initials: G
authors.lastname: Yang
authors.forename: Mihaela
authors.initials: M
authors.lastname: Necula
authors.forename: Alice
authors.initials: A
authors.lastname: Lau
authors.forename: Steven
authors.initials: S
authors.lastname: Finkbeiner
authors.forename: Charles
authors.initials: C
authors.lastname: Glabe
authors.forename: J Lawrence
authors.initials: JL
authors.lastname: Marsh
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Muchowski
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Thompson
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004195:Disease Models, Animal; D004330:Drosophila; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000188:drug therapy* / Q000235:genetics; D007736:Kynurenic Acid / Q000633:toxicity; D008751:Methylene Blue / Q000494:pharmacology* / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D018625:Microscopy, Atomic Force; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011597:Psychomotor Performance; D051381:Rats; D045442:Rotarod Performance Test; D014162:Transfection; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D007736:Kynurenic Acid; D008751:Methylene Blue