title: Induction of chemokines, MCP-1, and KC in the mutant huntingtin expressing neuronal cells because of proteasomal dysfunction.
abstract: Huntington's disease is a hereditary neurodegenerative disorder caused by an aberrant polyglutamine expansion in the amino terminus of the huntingtin protein. The resultant mutant huntingtin form aggregates in neurons and causes neuronal dysfunction and degeneration in many ways including transcriptional dysregulation. Here, we report that the expression of mutant huntingtin in the mouse neuroblastoma cell results in massive transcriptional induction of several chemokines including monocyte chemoattractant protein-1 (MCP-1) and murine chemokine (KC). The mutant huntingtin expressing cells also exhibit proteasomal dysfunction and down-regulation of NF-kappaB activity in a time-dependent manner and both these phenomena regulate the expression of MCP-1 and KC. The expression of MCP-1 and KC are increased in the mutant huntingtin expressing cells in response to mild proteasome inhibition. However, the expression of MCP-1 and KC and proteasome activity are not altered and inflammation is rarely observed in the brain of 12-week-old Huntington's disease transgenic mice in comparison with their age-matched controls. Our result suggests that the mutant huntingtin-induced proteasomal dysfunction can up-regulate the expression of MCP-1 and KC in the neuronal cells and therefore might trigger the inflammation process.
authors.affiliation: Cellular and Molecular Neuroscience Laboratory, National Brain Research Centre, Manesar, Gurgaon, India.
authors.forename: Swetha K
authors.initials: SK
authors.lastname: Godavarthi
authors.forename: Doronala
authors.initials: D
authors.lastname: Narender
authors.forename: Amit
authors.initials: A
authors.lastname: Mishra
authors.forename: Anand
authors.initials: A
authors.lastname: Goswami
authors.forename: Sudheendra N R
authors.initials: SN
authors.lastname: Rao
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Nukina
authors.forename: Nihar Ranjan
authors.initials: NR
authors.lastname: Jana
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis* / Q000235:genetics; D019742:Chemokines, CC / Q000096:biosynthesis* / Q000235:genetics; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D000071058:Huntingtin Protein; D015151:Immunoblotting; D007150:Immunohistochemistry; D016209:Interleukin-8 / Q000096:biosynthesis; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation / Q000502:physiology; D016328:NF-kappa B / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics* / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D014764:Viral Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D018932:Chemokine CCL2; D019742:Chemokines, CC; C086055:HTT protein, human; D000071058:Huntingtin Protein; D016209:Interleukin-8; C121662:MCK-1 protein, Mouse cytomegalovirus 1; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D014764:Viral Proteins; D020928:Mitogen-Activated Protein Kinases; D046988:Proteasome Endopeptidase Complex