title: Sulforaphane enhances proteasomal and autophagic activities in mice and is a potential therapeutic reagent for Huntington's disease.
abstract: The ubiquitin proteasome system (UPS) is impaired in Huntington's disease, a devastating neurodegenerative disorder. Sulforaphane, a naturally occurring compound, has been shown to stimulate UPS activity in cell cultures. To test whether sulforaphane enhances UPS function in vivo, we treated UPS function reporter mice ubiquitously expressing the green fluorescence protein (GFP) fused to a constitutive degradation signal that promotes its rapid degradation in the conditions of a healthy UPS. The modified GFP is termed GFP UPS reporter (GFPu). We found that both GFPu and ubiquitinated protein levels were significantly reduced and the three peptidase activities of the proteasome were increased in the brain and peripheral tissues of the mice. Interestingly, sulforaphane treatment also enhanced autophagy activity in the brain and the liver. To further examine whether sulforaphane promotes mutant huntingtin (mHtt) degradation, we treated Huntington's disease cells with sulforaphane and found that sulforaphane not only enhanced mHtt degradation but also reduced mHtt cytotoxicity. Sulforaphane-mediated mHtt degradation was mainly through the UPS pathway as the presence of a proteasome inhibitor abolished this effect. Taken together, these data indicate that sulforaphane activates protein degradation machineries in both the brain and peripheral tissues and may be a therapeutic reagent for Huntington's disease and other intractable disorders. Accumulation of mutant huntingtin (mHtt) protein causes Huntington's disease (HD). Sulforaphane (SFN), a naturally occurring compound, increased proteasome and autophagy activities in vivo and enhanced mHtt turnover and cell survival in HD cell models. SFN-mediated mHtt degradation is mainly through the proteasome pathway. These data suggest that SFN can be a therapeutic reagent for treating HD and other intractable disorders.
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, South Dakota, USA.
authors.forename: Yanying
authors.initials: Y
authors.lastname: Liu
authors.forename: Casey L
authors.initials: CL
authors.lastname: Hettinger
authors.forename: Dong
authors.initials: D
authors.lastname: Zhang
authors.forename: Khosrow
authors.initials: K
authors.lastname: Rezvani
authors.forename: Xuejun
authors.initials: X
authors.lastname: Wang
authors.forename: Hongmin
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism*; D017879:Isothiocyanates / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism*; D013454:Sulfoxides; D014162:Transfection
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D017879:Isothiocyanates; D009419:Nerve Tissue Proteins; D013454:Sulfoxides; D046988:Proteasome Endopeptidase Complex; C016766:sulforaphane
keywords: autophagy; mutant huntingtin; neurodegeneration; protein degradation; sulforaphane; ubiquitin proteasome system