Doublecortin-like kinase 3 (DCLK3), a novel striatum-enriched species, is amodulator of mutant huntingtin in vivo: L. GALVAN1, M.-C. GAILLARD2, M. DE CHALDÉE2, G. AUREGAN1, N.DUFOUR1, M. GUILLERMIER1, D. HOUITTE1, F. PETIT1, C. MALGORN1,G. LIOT3, S. HUMBERT3, J. ELALOUF2, N. DÉGLON1, *E. P. BROUILLET1;1CEA, MIRCen, URA CEA-CNRS 2210, Fontenay-aux-Roses, France; 2CEAIBITec-S/SBIGeM, Saclay, France; 3Inst. Curie, UMR 146, CNRS, Orsay, France
| Autor: | Galvan, Laurie, L., Galvan, M.-C., Gaillard, M. De, Chaldée, G., Auregan, N., Dufour, M., Guillermier, D., Houitte, F., Petit, C., Malgorn, G., Liot, S., Humbert, J., Elalouf, N., Déglon |
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| Přispěvatelé: | University of California [Los Angeles] (UCLA), University of California (UC) |
| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: | |
| Zdroj: | SFN 2009 SFN 2009, Oct 2009, CHICAGO, United States |
| Popis: | International audience; Huntington's disease (HD) is a neurodegenerative disorder caused by an abnormalCAG repeat expansion coding for an expanded polyglutamine tract in the protein"huntingtin" (Htt). Although this mutant Htt (mHtt) is expressed ubiquitouslythroughout the brain, the striatum is found preferentially affected. One hypothesisto explain this particular vulnerability is that striatal neurons express a particularset of proteins that make them highly vulnerable to mHtt. In order to furtherexamine this hypothesis, we carried out a transcriptome analysis of different brainterritories and identified more than 100 molecular markers i.e. transcripts that arehighly enriched in the mouse striatum. We recently focused our interest on asubset of striatal-enriched transcripts of poorly characterized transcripts.We here report the study of one of these markers, the CAMKII family-relatedkinase DCLK3. We found that DCLK3 is mainly expressed in the adult striatum inrodent with low level of expression in the newborn and striatal primary cultures.Reduced mRNA levels of DCLK3 were found in the striatum of transgenic mousemodels of HD. We thus studied the effect of DCLK3 overexpression and knockdownin a mouse model of HD using lentiviral vectors coding for a N-terminalfragment of mHtt. DCLK3 and its related siRNA were delivered using lentiviralvectors. Striatal degeneration produced by mHtt was characterized usingimmunohistochemistry of DARPP32, Cytochrome oxidase and ubiquitin followedby quantitative histological evaluation. Results showed that lenti-siRNA targetingDCLK3 increased mHtt toxicity when compared to the control. On the contrary,overexpression of DCLK3 reduced the striatal lesions produced by mHtt in vivo.DCLK3 also decreased the number and size of ubiquitin-containing nuclearinclusions. Current experiments are examining the mechanisms that could underliethe neuroprotective effect of DCLK3 in striatal neurons. The present study suggests that DCLK3 is a potential modifier of the disease and might beconsidered in HD therapy to slow disease progression. |
| Databáze: | OpenAIRE |
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