title: Ectoine alters subcellular localization of inclusions and reduces apoptotic cell death induced by the truncated Machado-Joseph disease gene product with an expanded polyglutamine stretch.
abstract: Protein misfolding is considered a key event in the pathogenesis of polyglutamine disease such as Machado-Joseph disease (MJD). Overexpression of chaperone proteins and the application of chemical chaperones are reported to suppress polyglutamine induced cytotoxicity in vitro and in vivo. The effects of compatible solutes, which are osmoprotectants in bacteria and possess the action in stabilizing proteins under stress, have not, to our knowledge, been studied. We explored the protective effects of the compatible solutes ectoine, hydroxyectoine, and betaine on apoptotic cell death produced by the truncated MJD gene product with an expanded polyglutamine tract in cultured neuro2a cells. Ectoine, but not hydroxyectoine or betaine, decreased large cytoplasmic inclusions and increased the frequency of nuclear inclusions. Immunoblot analysis showed that ectoine reduced the total amount of aggregates. Despite the presence of nuclear inclusions, apoptotic features were less frequently observed after ectoine application. Our findings suggest that ectoine, a natural osmoprotectant in bacteria, may function as a novel molecule protecting cells from polyglutamine-induced toxicity.
authors.affiliation: Department of Neurology, Institute of Clinical Medicine, Graduate School of Comprehensive Medical Sciences, University of Tsukuba, Tsukuba 305-8575, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Furusho
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Yoshizawa
authors.forename: Shinichi
authors.initials: S
authors.lastname: Shoji
mesh_terms: D000599:Amino Acids, Diamino / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D000067699:Ataxin-3; D001622:Betaine / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D005765:Gastrointestinal Agents / Q000494:pharmacology; D002479:Inclusion Bodies / Q000187:drug effects / Q000235:genetics / Q000473:pathology; D017827:Machado-Joseph Disease / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D009410:Nerve Degeneration / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D009687:Nuclear Proteins; D010455:Peptides / Q000037:antagonists & inhibitors / Q000633:toxicity; D017510:Protein Folding; D012097:Repressor Proteins; D014157:Transcription Factors; D019680:Trinucleotide Repeat Expansion / Q000187:drug effects / Q000235:genetics
chemical_list: D000599:Amino Acids, Diamino; D005765:Gastrointestinal Agents; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; D010455:Peptides; D012097:Repressor Proteins; D014157:Transcription Factors; C097188:polyglutamine; D001622:Betaine; C045628:ectoine; C092341:ATXN3 protein, human; D000067699:Ataxin-3; C511594:Atxn3 protein, mouse