Huntingtin and the control of long distance transport of synaptic / extrasynaptic signals in health and disease

• Applicant: Dr. Michael R. Kreutz
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2014 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 258728186

• Final Report Year: 2020

Final Report Abstract

Huntingtin (HTT) the protein that when mutated causes Huntington’s disease (HD), a devastating neurological disorder, acts as a scaffold for protein complexes with an emerging role in the transport of vesicles and proteins in axons and dendrites. At an early stage of the disease no structural damage exists but rather an impairment of synaptic function that manifests in a shift from synaptic to extrasynaptic N-Methyl-D-Aspartate-receptor (NMDAR) signalling. Jacob is a synapto-nuclear protein messenger that encodes and transduces the synaptic or extra-synaptic origin of NMDAR signals to the nucleus and that plays a role in regulation of gene expression either leading to cell death or promoting cell survival and synaptic plasticity. Nuclear trafficking of Jacob requires an active importin- and dynein-mediated retrograde transport along microtubules. Several studies have provided compelling evidence that HTT interacts with proteins which are involved in gene transcription, cell signaling and intracellular transport. Very recent reports suggest that HTT might provide a platform that links transcriptional regulators to molecular motors for transport from synapse to nucleus. With this proposal we wanted to address the idea that HTT and Jacob could play a major role in integrating long-range signals from the synapse to the nucleus and consequently will modify gene expression in health and in HD. We assumed that a functional interplay between Jacob, a protein that can dock an NMDAR-derived signalosome to nuclear target sites and mutant HTT might contribute to neurodegeneration in HD. We wanted to test whether HTT and Jacob interact directly and we aimed to determine whether extrasynaptic NMDAR trigger nuclear import of Jacob in HD and how this relates to cell death and neurodegeneration. The work was funded by a ANR/DFG collaboration grant. The collaboration involved the lab of Prof. Frederic Saudou at the Grenoble Institute of Neuroscience (GIN).

Publications

• An Importin Code in neuronal transport from synapse-to-nucleus? Front Mol Neurosci. 2015 8:33
  Lever MB, Karpova A, Kreutz MR
  
• A Dendritic Golgi Satellite between ERGIC and Retromer. Cell Rep. 2016 14(2):189-99
  Mikhaylova M, Bera S, Kobler O, Frischknecht R, Kreutz MR
  
• A Jacob/Nsmf Gene Knockout Results in Hippocampal Dysplasia and Impaired BDNF Signaling in Dendritogenesis. PLoS Genet. 2016 2(3):e1005907
  Spilker C, Nullmeier S, Grochowska KM, Schumacher A, Butnaru I, Macharadze T, Gomes GM, Yuanxiang P, Bayraktar G, Rodenstein C, Geiseler C, Kolodziej A, Lopez-Rojas J, Montag D, Angenstein F, Bär J, D'Hanis W, Roskoden T, Mikhaylova M, Budinger E, Ohl FW, Stork O, Zenclussen AC, Karpova A, Schwegler H, Kreutz MR
  
• A plasmid-based expression system to study proteinprotein interactions at the Golgi in vivo. Anal Biochem. 2016 502:50-52
  Bera S, Raghuram V, Mikhaylova M, Kreutz MR
  
• Dopamine agonists rescue Aβinduced LTP impairment by Src-family tyrosine kinases. Neurobiol Aging. 2016 40:98-102
  Yuan Xiang P, Janc O, Grochowska KM, Kreutz MR, Reymann KG
  
• Mature granule cells of the dentate gyrus--Passive bystanders or principal performers in hippocampal function? Neurosci Biobehav Rev. 2016 64:167-74
  Lopez-Rojas J, Kreutz MR
  
• Plasticity of intrinsic excitability in mature granule cells of the dentate gyrus. Sci Rep. 2016 6:21615
  Lopez-Rojas J, Heine M, Kreutz MR
  
• Proteomics of the Synapse--A Quantitative Approach to Neuronal Plasticity. Mol Cell Proteomics. 2016 15(2):368-81
  Dieterich DC, Kreutz MR
  
• Ring finger protein 10 is a novel synaptonuclear messenger encoding activation of NMDA receptors in hippocampus. Elife. 2016 5:e12430
  Dinamarca MC, Guzzetti F, Karpova A, Lim D, Mitro N, Musardo S, Mellone M, Marcello E, Stanic J, Samaddar T, Burguière A, Caldarelli A, Genazzani AA, Perroy J, Fagni L, Canonico PL, Kreutz MR, Gardoni F, Di Luca M
  
• Synaptic GluN2B/CaMKII-α Signaling Induces Synapto-Nuclear Transport of ERK and Jacob. Front Mol Neurosci. 2016 9:66
  Melgarejo da Rosa M, Yuanxiang P, Brambilla R, Kreutz MR, Karpova A
  
• Synaptonuclear messenger PRR7 inhibits c-Jun ubiquitination and regulates NMDA- mediated excitotoxicity. EMBO J. 2016 35(17):1923-34
  Kravchick DO, Karpova A, Hrdinka M, Lopez-Rojas J, Iacobas S, Carbonell AU, Iacobas DA, Kreutz MR, Jordan BA
  
• What do we learn from the murine Jacob/Nsmf gene knockout for human disease? Rare Dis. 2016 4(1):e1241361
  Spilker C, Grochowska KM, Kreutz MR
  
• Posttranslational modification impact on the mechanism by which amyloidβ induces synaptic dysfunction. EMBO Rep. 2017 18:962-981
  Grochowska KM, Yuanxiang P, Bär J, Raman R, Brugal G, Sahu G, Schweizer M, Bikbaev A, Schilling S, Demuth HU, Kreutz MR
  
• Predator odor evokes sex-independent stress responses in male and female Wistar rats and reduces phosphorylation of cyclic-adenosine monophosphate response element binding protein in the male, but not the female hippocampus. Hippocampus. 2017 27(9):1016-1029
  Homiack D, O'Cinneide E, Hajmurad S, Barrileaux B, Stanley M, Kreutz MR, Schrader LA
  
• The Segregated Expression of Voltage-Gated Potassium and Sodium Channels in Neuronal Membranes: Functional Implications and Regulatory Mechanisms. Front Cell Neurosci. 2017 11:115
  Duménieu M, Oulé M, Kreutz MR, Lopez-Rojas J
  
• Neuronal DNA Methyltransferases: Epigenetic Mediators between Synaptic Activity and Gene Expression? Neuroscientist. 2018 24(2):171-185
  Bayraktar G, Kreutz MR