Expanded huntingtin activates the C-JUN N TERMINAL KINASE/C-JUN pathway prior to aggregate formation in striatal neurons in culture
Section snippets
Primary striatal cultures
All experiments on animals were performed in accordance with the guidelines of the French Agriculture and Forestry Ministry for handling animals. Experiments were designed in order to minimize the number and the suffering of all animals used.
Striata were dissected out from 14 days old embryos from pregnant Swiss mice (Janvier, Le Genest Saint Isle, France). This stage was chosen because it corresponds to the end of the mitotic phase of striatal neurons, and allows the differentiation of these
Results
Primary cultures of striatal neurons were transiently transfected with two constructs encoding the exon 1 of the human Htt containing 25 or 103 glutamine repetition coupled with GFP (GFP-Htt Ex1-25Q, -103Q), and representing the wild type and the mutated forms of the fragment, respectively. These constructs were chosen because i) genetic studies from transgenic mouse model for HD have shown that the expanded exon 1 of human Htt (Exp-Htt Ex1) gene is sufficient to cause a HD-like phenotype (
Discussion
We show in the present work that activation of the JNK/c-Jun module is part of a cascade of events involved in striatal death induced by Exp-Htt exon 1. A significant increase of c-Jun phosphorylation and induction was observed in Exp-Htt exon 1 expressing striatal neurons. In this population, c-Jun activation and induction was an early event in the neurodegenerative process, occurring prior to nuclear aggregate formation. Furthermore, a dominant negative version of c-Jun and a selective JNK
Conclusion
Our data provide the first evidence that inhibition of the JNK/c-Jun module can protect, at least in part, from striatal neuron degeneration in HD. Of course, our data need to be confirmed in more sophisticated model systems, which could take into account the environmental complexity of striatal neurons, for example cortical glutamatergic or nigral dopaminergic afferences. The striatum receives the densest dopaminergic innervation in the brain and dopamine is toxic to striatal neurons in vitro
Acknowledgements
This work was supported by CNRS, University Pierre et Marie Curie and Fondation Schueller-Bethencourt for J. Caboche. M. Garcia was supported by the Ministère de l'Education, de la Recherche et de la Technologie and Fondation pour la Recherche Médicale. D. Charvin was supported by the Ministère de l'Education, de la Recherche et de la Technologie. We acknowledge M. Yaniv for the Δ-c-Jun plasmid, and HDF Resource Bank, UCLA for the GFP tagged versions (25Q and 103Q) of human exon 1 of huntingtin.
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Cited by (34)
Cellular and Molecular Mechanisms of Neuronal Dysfunction in Huntington's Disease
2016, Handbook of Behavioral NeuroscienceCitation Excerpt :In particular, cultures of striatal neurons from R6/2 HD mice are sensitized to DA-induced oxidative stress, leading to neuronal autophagy (Petersen et al., 2001). ROS produced by low doses of DA potentiate activation of the proapoptotic JNK pathway induced by Exp-HTT (Charvin et al., 2005; Garcia et al., 2004; see Fig. 45.1). Conversely, pharmacological inhibition of this pathway is neuroprotective in the R6/2 transgenic mouse model of HD (Apostol et al., 2008).
Ethyl pyruvate ameliorates 3-nitropropionic acid-induced striatal toxicity through anti-neuronal cell death and anti-inflammatory mechanisms
2014, Brain, Behavior, and ImmunityThe transition metals copper and iron in neurodegenerative diseases
2010, Chemico-Biological InteractionsCitation Excerpt :It is caused by the expansion of an unstable CAG trinucleotide repeat within the first exon of the IT-15 gene encoding huntingtin (Htt) protein [208,209]. The function of Htt protein has not been completely elucidated; however, it is possibly involved in endocytosis, vesicular trafficking [210], embryonic development [211] and transcriptional regulation [212]. The CAG repeat in Htt shows between 10 and 29 copies in healthy subjects and it is expanded to 36–121 in HD [213].
Implication of the JNK pathway in a rat model of Huntington's disease
2009, Experimental NeurologyCEP-1347 reduces mutant huntingtin-associated neurotoxicity and restores BDNF levels in R6/2 mice
2008, Molecular and Cellular NeuroscienceGranulocyte-colony stimulating factor attenuates striatal degeneration with activating survival pathways in 3-nitropropionic acid model of Huntington's disease
2008, Brain ResearchCitation Excerpt :3NP induces JNK activation and c-Jun expression in the striatum and 3NP-induced striatal death is controlled by the activation of the JNK pathway (Garcia et al., 2002). In HD, mutated huntingtin can activate JNK in hippocampal cells (Liu et al., 2000; Apostol et al., 2007) and in striatal neuronal cells via mechanisms similar to those observed in 3NP experimental models (Garcia et al., 2002; Garcia et al., 2004). Damage to mitochondria by neurotoxins forms more ROS from the electron transporter chain and provokes oxidative damage that modifies proteins and other biomolecules (Halliwell, 2006).
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Present address: Venetian Institute of Molecular Medicine and Department of Biomedical Sciences, University of Padova, 35121 Padova, Italy.