title: Activation of Elk-1 participates as a neuroprotective compensatory mechanism in models of Huntington's disease.
abstract: The transcription factor Elk-1 has been revealed as neuroprotective against toxic stimuli. In this study, we explored the neuroprotective capacity of Elk-1 in Huntington's disease. To this aim, we used two exon-1 mutant huntingtin (mhtt) mouse models (R6/1 and R6/2), and a full-length mhtt striatal cell model (STHdh(Q111/Q111) ). Analysis of Elk-1 and pElk-1(Ser383) in the striatum of R6 mice revealed increased levels during the disease progression. Similarly, Elk-1 and pElk-1(Ser383) levels were increased in STHdh(Q111/Q111) cells when compared with wild-type cells. In addition, we observed a predominant nuclear localization of Elk-1 in STHdh(Q111/Q111) cells, and in the striatum of 30-week-old R6/1 mice. Nuclear Elk-1 did not colocalize with mhtt aggregates, suggesting a higher transcriptional activity. In agreement, the knock-down of Elk-1 decreased immediate early genes expression in STHdh(Q111/Q111) cells, but not in wild-type cells. Interestingly, reduction of Elk-1 levels by siRNAs transfection promoted cell death and caspase 3 cleavage in STHdh(Q111/Q111) cells, but not in wild-type cells. In summary, we propose that increased protein levels, phosphorylation and nuclear localization of Elk-1 observed in exon-1 and full-length Huntington's disease models could be a compensatory mechanism activated by striatal cells in response to the presence of mhtt that contributes to neuroprotection.
authors.affiliation: Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Anglada-Huguet
authors.forename: Albert
authors.initials: A
authors.lastname: Giralt
authors.forename: Esther
authors.initials: E
authors.lastname: Perez-Navarro
authors.forename: Jordi
authors.initials: J
authors.lastname: Alberch
authors.forename: Xavier
authors.initials: X
authors.lastname: Xifró
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001711:Biotransformation / Q000502:physiology; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D003342:Corpus Striatum / Q000166:cytology / Q000502:physiology; D003600:Cytosol / Q000378:metabolism; D018450:Disease Progression; D051767:Early Growth Response Protein 2 / Q000235:genetics; D016762:Genes, fos / Q000187:drug effects; D006801:Humans; D006816:Huntington Disease / Q000235:genetics* / Q000473:pathology*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009154:Mutation / Q000502:physiology; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D014162:Transfection; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism*
chemical_list: D051767:Early Growth Response Protein 2; C497327:Egr2 protein, mouse; C494113:Elk1 protein, mouse; D034741:RNA, Small Interfering; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D050807:ets-Domain Protein Elk-1