title: Loss of striatal 90-kDa ribosomal S6 kinase (Rsk) is a key factor for motor, synaptic and transcription dysfunction in Huntington's disease.
abstract: Huntington's disease (HD) is characterized by motor dysfunction due to the expression of mutant huntingtin that promotes degeneration of striatal GABAergic medium-sized spiny neurons. Here we explore the role of the 90-kDa ribosomal S6 kinase (Rsk) in the physiopathology of HD. First, we show a reduction of Rsk1 and 2 protein levels in the striatum of two HD mouse models, R6/1 and Hdh(Q7/Q111) knock-in mice, at ages when they suffer from motor disturbances. Interestingly, the analysis of post-mortem samples from HD patients revealed a significant reduction of both Rsk forms in the putamen and caudate, but not in the cortex. Rsk1 and 2 levels were also reduced in the striatum of BDNF heterozygous mice, and upon BDNF neutralization in striatal cultures, suggesting that striatal loss of BDNF could be involved in the decrease of Rsk levels. Finally, we injected recombinant adeno-associated-virus (AAV5)-Rsk in the striatum of R6/1 mice at the onset of motor symptoms. Four weeks later, we found higher Rsk levels in the striatum accompanied by improvements in motor coordination, enhanced expression of synaptic markers and increased expression of genes related to synaptic plasticity, such as cfos and egr1. Altogether, we identified Rsk as a key factor in striatal alterations associated with motor deficits in HD.
authors.affiliation: Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain. Electronic address: marta.anglada@dzne.de.
authors.forename: Marta
authors.initials: M
authors.lastname: Anglada-Huguet
authors.affiliation: Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain. Electronic address: albert.giralt@inserm.fr.
authors.forename: Albert
authors.initials: A
authors.lastname: Giralt
authors.affiliation: Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain. Electronic address: laurarue@gmail.com.
authors.forename: Laura
authors.initials: L
authors.lastname: Rué
authors.affiliation: Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain. Electronic address: alberch@ub.edu.
authors.forename: Jordi
authors.initials: J
authors.lastname: Alberch
authors.affiliation: Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain; TargetsLab, Departament de Ciències Mèdiques, Facultat de Medicina, Universitat de Girona, Girona, Spain. Electronic address: xavier.xifro@ub.edu.
authors.forename: Xavier
authors.initials: X
authors.lastname: Xifró
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D005786:Gene Expression Regulation; D055879:Gene Knock-In Techniques; D006801:Humans; D000071058:Huntingtin Protein / Q000235:genetics; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D008810:Mice, Inbred C57BL; D009043:Motor Activity; D009154:Mutation; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics* / Q000378:metabolism; D013569:Synapses / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015533:Transcriptional Activation
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D000071058:Huntingtin Protein; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3
keywords: BDNF; Huntingtin; PSD95; R6/1 mouse; Striatum; VGlut1