Inter-University Attraction Poles Phase VII P7/16 Network: An integrated approach towards understanding the pathogenesis of neurodegeneration





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Work Package 3: Cell Biology and model organisms


Partners


Leader: Ludo Van Den Bosch, Jean-Noël Octave
Co-Leader: Bart De Strooper, Wim Robberecht
Belgian Parners: Wim Annaert, Carlos Dotti, Patrik Verstreken, Amantha Thathiah, Debby Van Dam, Philip Van Damme, Pascal Kienlen-Campard, Ilse Dewachter
European Parners: Paul Saftig, Bart Dermaut, Jean-Charles Lambert
Associated Parners: Jean-Pierre Brion, Stuart Maudsley

Aims

  1. The effects of genes associated with sporadic AD on APP processing– a model for sporadic AD
    PSEN1 (yellow) complexes are sorted from the TGN to the cell surface, likely via the Rab11-positive recycling compartments. In contrast, interaction with AP-1 via a conserved ERTSLM motif allows PSEN2 (red) complexes to be sorted to LE/LYS, probably via EEs/sorting endosomes. Phosphorylation of Ser19 affects PSEN2 sorting. Mutation to Ala confers a more strict localization in LE/LYS and TGN (red dashed arrow). Substituting Ser19 to Asp (phosphomimetic) decreases binding and results in a more randomized distribution. Changing critical residues in the motif (AxxxAA) fully prevents AP-1 binding, resulting in ‘‘default’’ sorting of PSEN2/γ-secretase along the PSEN1/γ-secretase transport route (red dashed arrow). LE/LYS localization of PSEN2/γ-secretase accounts for a major pool of intracellular Aβ, wherein relative Aβ42 levels become strongly increased by FAD mutations (Sannerud et al. 2016).

  2. Endosomal dysfunction and lysosomal clearance in Alzheimer disease
    Stepwise autophagy progression in AD-affected neurons. Adapted from Peric and Annaert, Acta Neuropathol., 2015.

  3. Abnormal lipid metabolism and Alzheimer Disease
  4. Signaling networks around APP
  5. Aging genes selected by bioinformatics approaches affecting APP processing
  6. Mechanisms of tau-associated toxicity in cellular and animal models
  7. Analysis of the role of the micro-RNA’ome in sporadic AD
  8. Interactors and functions of Parkinson genes
    Schematic representation of the role of NdufA10 in complex I. NdufA10 is located in subunit I within the membrane arm domain of complex I in close vicinity to the ubiquinone binding pocket.

  9. The pathophysiological role of α-synuclein aggregation in models for Parkinson disease
  10. Analysis of GBA deficient mice and potential links to the endosomal/lysosome system
  11. The role of deubiquitinases in parkin-mediated mitophagy and Parkinson disease
  12. Study of TDP-43 and FUS/TLS in FTLD and Amyothropic lateral sclerosis
    Overexpression of mutant human TDP-43 leads to a dose- dependent motor phenotype. a. Overexpression of mutant TDP-43 induced an abnormal hindlimb reflex (arrows) at variable ages dependent on the TDP-43 dose that was absent in non-transgenic (Ntg) mice and Mt-TAR5/5 mice express- ing a low TDP-43 dose. b. Typical example of an end-stage paralysis in Mt-TAR6/6 mice. c. About 5 % of end-stage hemizygous Mt- TAR6 mice developed severe paralysis of the hindlimbs and acquired a swimming gait. Adapted from Janssens et al., Molecular Neurobiology, 2013.

  13. The biology of progranulin in neurodegeneration
  14. Mechanism of neurodegeneration induced by hexanucleotide repeats in C9ORF72
    Overview of the RNAi screen targeting nuclear transport in an in vivo Drosophila model expressing arginine containing DPRs. Green indicates suppressors and red enhancers.