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

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Work Package 5: Translational Research


Leader: Sebastiaan Engelborghs
Co-Leader: Kristel Sleegers, Julie van der Zee
Belgian Parners: Debby Van Dam, Philip Van Damme, Ilse Dewachter
European Parners: Paul Saftig


  1. To develop and validate genomic-based biomarkers for AD, related dementias, ALS and FTLD
    Left upper panel: Relative glucose metabolism in ALS versus controls Surface and interhemispheric projections of areas with relative hypometabolism (red) and hypermetabolism (blue) for patients with ALS versus healthy control cases using voxel-based analysis (Pheight < .001). Right upper panel: Extensive hypometabolism in frontotemporal areas is a negative predictor of outcome in ALS. Left lower panel: SVM Voxel-based discriminant analysis feature weights of the classifier for ALS versus healthy control cases projected onto a normalized structural magnetic resonance image in Montreal Neurological Institute space. The scale of the feature weights represents how much a voxel contributes. The scale was normalized so that the sum of all weights is 1. Only voxels with a weight of more than 0.002 in absolute value are shown. Clusters indicate areas with high discriminative impact based on relative hypometabolism (yellow-red) and relative hypermetabolism (blue). Right lower panel: SVM Voxel-based discriminant analysis plots of distance to the classifier for healthy control cases (green) versus patients with ALS using a leave-one-out approach.

  2. To study heterogeneity and control of gamma-secretase to generate safer and better medication for AD
  3. To contribute to the understanding of the mechanism of ALS and FTLD and to the development of therapeutic strategies for them:
    • assess the therapeutic potential of GRN in rodent models with mutant TDP-43 induced neurodegeneration
    • to identify modifiers that rescue the phenotype induced by wild-type or mutant FUS/TLS
    • explore whether pharmacological inhibition of Notch may affect the motor neuron degeneration of SOD1G93A mice
    A. Flies expressing hFUS in motor neurons display severe eclosion defects and wing expansion phenotypes. B. Adult expression of hFUS in motor neurons significantly shortens life span of the mutant flies. C. Flies expressing hFUS in motor neurons display age-dependent motor performance decline. D. Quantification of the number of motor neurons at day 0 and 8 in the T1/T2 border of the ventral nerve cord of control and mutant FUS expressing flies.