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Series GSE104091 Query DataSets for GSE104091
Status Public on Mar 22, 2018
Title The striatal kinase DCLK3 produces neuroprotection against mutant huntingtin
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary The neurobiological functions of a number of kinases expressed in the brain are unknown. Here, we report new findings on DCLK3 (Doublecortin-like kinase 3) which is preferentially expressed in neurons in the striatum and dentate gyrus. Its function has never been investigated. DCLK3 expression is markedly reduced in Huntington's disease. Recent data obtained in studies related to cancer suggest DCLK3 could have anti-apoptotic effect. Thus, we hypothesized that early loss of DCLK3 in Huntington's disease may render striatal neurons more susceptible to mutant huntingtin (mHtt). We discovered that DCLK3 silencing in the striatum of mice exacerbated the toxicity of an N-terminal fragment of mHtt. Conversely, overexpression of DCLK3 reduced neurodegeneration produced by mHtt. DCLK3 also produced beneficial effects on motor symptoms in a knock-in mouse model of Huntington's disease. Using different mutants of DCLK3, we found that the kinase activity of the protein plays a key role in neuroprotection. To investigate the potential mechanisms underlying DCLK3 effects, we studied the transcriptional changes produced by the kinase domain in human striatal neurons in culture. Results show that DCLK3 regulates in a kinase-dependent manner the expression of many genes involved in transcription regulation and nucleosome/chromatin remodeling. Consistent with this, histological evaluation showed DCLK3 is present in the nucleus of striatal neurons and, protein-protein interaction experiments suggested that the kinase domain interacts with zinc finger proteins, including TADA3, a core component of SAGA complex. Our novel findings suggest that the presence of DCLK3 in striatal neurons may play a key role in transcription regulation and chromatin remodeling in these brain cells, and show that reduced expression of the kinase in Huntington’s disease could render the striatum highly vulnerable to neurodegeneration.
Examination of DCLK3 as neuroprotector against mutant huntingtin in vivo and in vitro models.
Overall design Examination of DCLK3 as neuroprotector against mutant huntingtin in vitro experiments.
Contributor(s) Brouillet E, Galvan L, Francelle L, Gaillard M, de Longprez L, Carrillo-de Sauvage M, Liot G, Cambon K, Stimmer L, Luccantoni S, Flament J, Valette J, de Chaldée M, Auregan G, Guillermier M, Joséphine C, Petit F, Jan C, Jarrige M, Dufour N, Elalouf J, Bonvento G, Humbert S, Saudou F, Hantray P, Merienne K, Bemelmans A, Perrier AL, Déglon N
Citation(s) 29534157, 34278269
Submission date Sep 21, 2017
Last update date Jul 20, 2021
Phone +33169908529
Organization name I-Stem/INSERM U861
Street address 28, Rue Henri Desbruères
City Corbeil-Essonnes
ZIP/Postal code 91100
Country France
Platforms (1)
GPL17303 Ion Torrent Proton (Homo sapiens)
Samples (12)
GSM2789665 MSN LV-GFP n1 (G1)
GSM2789666 MSN LV-GFP n2 (G2)
GSM2789667 MSN LV-GFP n3 (G3)
BioProject PRJNA408232
SRA SRP118468

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Supplementary file Size Download File type/resource
GSE104091_Galvan_Brouillet_et_al_DCLK3-2017_DCLK3_gene_reads_count_normalized_RPM.txt.gz 1.3 Mb (ftp)(http) TXT
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