Huntington's disease (HD) is a neurodegenerative disorder caused by an abnormal CAG repeat expansion coding for an expanded polyglutamine tract in the protein "huntingtin" (Htt). Although this mutant Htt (mHtt) is expressed ubiquitously throughout the brain, the striatum is found preferentially affected. One hypothesis to explain this particular vulnerability is that striatal neurons express a particular set of proteins that make them highly vulnerable to mHtt. In order to further examine this hypothesis, we carried out a transcriptome analysis of different brain territories and identified more than 100 molecular markers i.e. transcripts that are highly enriched in the mouse striatum. We recently focused our interest on a subset of striatal-enriched transcripts of poorly characterized transcripts. We here report the study of one of these markers, the CAMKII family-related kinase DCLK3. We found that DCLK3 is mainly expressed in the adult striatum in rodent with low level of expression in the newborn and striatal primary cultures. Reduced mRNA levels of DCLK3 were found in the striatum of transgenic mouse models of HD. We thus studied the effect of DCLK3 overexpression and knockdown in a mouse model of HD using lentiviral vectors coding for a N-terminal fragment of mHtt. DCLK3 and its related siRNA were delivered using lentiviral vectors. Striatal degeneration produced by mHtt was characterized using immunohistochemistry of DARPP32, Cytochrome oxidase and ubiquitin followed by quantitative histological evaluation. Results showed that lenti-siRNA targeting DCLK3 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 nuclear inclusions. Current experiments are examining the mechanisms that could underlie the neuroprotective effect of DCLK3 in striatal neurons. The present study suggests that DCLK3 is a potential modifier of the disease and might be considered in HD therapy to slow disease progression.