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2010001M06rik (St102) protects striatal neurons against an N-terminal fragmentof mutant huntingtin in vivo
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International audience. The mechanisms underlying the preferential vulnerability of striatal neurons to mutant Huntingtin (mHtt) in Huntington's disease (HD) remain unknown. Our hypothesis, supported by recent publications, is that genes selectively expressed in the striatum may play a role in this susceptibility to mHtt. In the present study we focused on a product of the 2010001M06rik (St102) gene, previously identified based on its preferential expression in the striatum and its significantly reduced levels in the striatum of R6/2 mice (Brochier et al., Physiol Genomics, 2008). We examined whether modifying St102 expression could change the neurotoxic effects of an N-terminal fragment of mHtt expressed in the mouse striatum using the HD lentiviral model (LV-Htt171-82Q). We developed lentiviral vectors to overexpress St102 (LV-St102) or knock-down St102 using a selective shRNA (LV-shRNA-St102). RT-PCR analysis infection of the striatum of adult mice with LV-St102 or LV-shRNA-St102 led to a significant increase or decrease of St102 expression respectively, without producing overt alterations as assessed using immunohistochemistry (IHC) of NeuN and DARPP32. LV-St102 and LV-shRNA-St102 were co-injected with LV-Htt171-82Q in the striatum of adult WT mice. Six weeks after injections, LV-Htt171-82Q consistently produced striatal lesions characterized by a loss of NeuN and DARPP32. Interestingly, the co-expression of Htt171-82Q and shRNA-St102 led to a significant increase in the lesion volume. On the contrary, the co-expression of Htt171-82Q and St102 overexpression led to a significant decrease of the lesion size. These results suggest that the loss of St102 expression could play a role in striatal degeneration in HD.
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