Inter-University Attraction Poles Phase VII P7/16 Network: An integrated approach towards understanding the pathogenesis of neurodegeneration
Work Package 3: Cell Biology and model organisms
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
- 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).
- Endosomal dysfunction and lysosomal clearance in Alzheimer disease
||Stepwise autophagy progression in AD-affected neurons. Adapted from Peric and Annaert, Acta Neuropathol., 2015.
- Abnormal lipid metabolism and Alzheimer Disease
- Signaling networks around APP
- Aging genes selected by bioinformatics approaches affecting APP processing
- Mechanisms of tau-associated toxicity in cellular and animal models
- Analysis of the role of the micro-RNA’ome in sporadic AD
- 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.
- The pathophysiological role of α-synuclein aggregation in models for Parkinson disease
- Analysis of GBA deficient mice and potential links to the endosomal/lysosome system
- The role of deubiquitinases in parkin-mediated mitophagy and Parkinson disease
- 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.
- The biology of progranulin in neurodegeneration
- 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.