The striatal kinase DCLK3 produces neuroprotection against mutant huntingtin.

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Version: Final published version
License: CC BY-NC 4.0
Serval ID
serval:BIB_A967A49D88F5
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
The striatal kinase DCLK3 produces neuroprotection against mutant huntingtin.
Journal
Brain
Author(s)
Galvan L., Francelle L., Gaillard M.C., de Longprez L., Carrillo-de Sauvage M.A., 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., Bonvento G., Humbert S., Saudou F., Hantraye P., Merienne K., Bemelmans A.P., Perrier A.L., Déglon N., Brouillet E.
ISSN
1460-2156 (Electronic)
ISSN-L
0006-8950
Publication state
Published
Issued date
01/05/2018
Peer-reviewed
Oui
Volume
141
Number
5
Pages
1434-1454
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
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 an 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 remodelling. 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 the transcriptional activator adaptor TADA3, a core component of the Spt-ada-Gcn5 acetyltransferase (SAGA) complex which links histone acetylation to the transcription machinery. Our novel findings suggest that the presence of DCLK3 in striatal neurons may play a key role in transcription regulation and chromatin remodelling in these brain cells, and show that reduced expression of the kinase in Huntington's disease could render the striatum highly vulnerable to neurodegeneration.
Keywords
Animals, Cells, Cultured, Corpus Striatum/enzymology, Disease Models, Animal, Down-Regulation/genetics, Electron Transport Complex IV/metabolism, Hand Strength/physiology, Huntingtin Protein/genetics, Huntington Disease/genetics, Huntington Disease/therapy, Macaca fascicularis, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity, Mutation/genetics, Neurons/metabolism, Phosphopyruvate Hydratase/metabolism, Protein-Serine-Threonine Kinases/genetics, Protein-Serine-Threonine Kinases/metabolism, RNA, Small Interfering/genetics, RNA, Small Interfering/metabolism, Trans-Activators/genetics, Trans-Activators/metabolism, Transcription Factors/genetics, Transcription Factors/metabolism
Pubmed
Web of science
Open Access
Yes
Create date
15/03/2018 17:56
Last modification date
20/08/2019 15:13
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