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Wim Annaert
Membrane Trafficking
VIB Department of Molecular and Developmental Genetics, K.U.Leuven
PhD: Univ. of Antwerp, Antwerp, Belgium, '93
Postdoc: Yale Univ., Connecticut, USA, '94-'96
VIB Group leader since 2001 |
e-mail
phone +32 16 33 05 20
ADDRESS |
Current team members
Group leader: Wim Annaert
Postdoctoral scientists: Cary Esselens, Dragana Spasic, Milos Spasic, Ragna Sannerud, Tim Raemaekers
Ph.D. Students: Aleksandar Peric, Applonia Josephine Rose, Arun Kumar Tharkeshwar Raghunath, Deepak Thimiri, Katherine Ivanova, Katrijn Coen
Support personnel: Christine Michiels, Genia De Brauwer, Hui Qi Lu, Ilse Declerck, Veerle Baert, Wendy Vermeire
Keywords
Alzheimer’s disease – Congenital disorders of Glycosylation – ER-Golgi/endosomal trafficking – APP - gamma-secretase
Science
Our laboratory is focused on understanding the molecular biology of membrane transport in a disease-related context covering Alzheimer’s disease and congenital disorders of glycosylation type II.
Related to Alzheimer’s, APP cleavage by γ-secretase leads to amyloid b peptide production, one possible cause of Alzheimer’s symptoms. γ-secretase is composed of four proteins—presenilin, nicastrin, PEN-2, and APH-1—which must come together for cleavage activity. Starting from the idea that Alzheimer’s disease might be slowed by inhibiting γ-secretase, we have now identified an endogenous inhibitor that prevents γ-secretase complex assembly and activity and thus might be targeted for therapy (Spasic et al., 2007). Although all four components are present in the ER, their assembly into functional γ-secretase is somehow restricted. Assembly begins with the binding of nicastrin to APH-1. This binding is competed early in the secretion pathway by Rer1p, a membrane receptor that retrieves proteins from the Golgi back to the ER. Rer1p binds to nicastrin, thus interfering with nicastrin’s ability to bind APH-1. Decreasing the amount of Rer1p led to an increase in γ-secretase activity. Exactly what triggers Rer1p to release nicastrin and allow it to bind to APH-1, and subsequently to the other γ-secretase components, remains to be determined. Preventing this release might provide a means to reduce γ-secretase activity and thus amyloid plaque formation.
Sporadic Alzheimer’s disease is also characterized by dysfunctions in the neuronal endo-lysosomal system. In this context, we hypothesize that the differential localization of distinct y-secretase complexes and substrates at the cell surface and endosomes is part of the mechanism defining specificity in intramembrane proteolysis. We are currently applying high resolution confocal microscopy to resolve this microdomain association of APP and y-secretase components. In addition we use superparamagnetic nanoparticles for neuronal endosomal targeting. Magnetic isolation followed by ‘organellar proteomics’ will generate proteome inventories of axonal and dendritic endosomal carriers and identify novel early biomarkers for endosomal dysfunction in Alzheimer’s disease and beyond. In a related line of research we are screening a 10K small compound library for their effects on inducing axonal and dendritic outgrowth/arborization using a medium-to-high throughput InCell1000 system.
In CDG-II, we identified mutations in subunits of the COG complex which are used now to study the role of this complex in maintaining Golgi-integrity. In a collaborative effort we also identified patients with mutations in a subunit of the V-ATPase linking pH-dependency to proper glycosylation
Selected Publications
De Strooper B, Annaert W
Novel Research Horizons for Presenilins and gamma-Secretases in Cell Biology and Disease
ANNU REV CELL DEV BI e-pub, e-pub, 2010
Spasic D, Raemaekers T, Dillen K, Declerck I, Baert V, Serneels L, Fullekrug J, Annaert W
Rer1p competes with APH-1 for binding to nicastrin and regulates {gamma}-secretase complex assembly in the early secretory pathway
J CELL BIOL 176, 629-40, 2007
Spasic D, Tolia A, Dillen K, Baert V, De Strooper B, Vrijens S, Annaert W
Presenilin-1 Maintains a Nine-Transmembrane Topology throughout the Secretory Pathway
J BIOL CHEM 281, 26569-77, 2006
Esselens C, Oorschot V, Baert V, Raemaekers T, Spittaels K, Serneels L, Zheng H, Saftig P, De Strooper B, Klumperman J, Annaert W
Presenilin 1 mediates the turnover of telencephalin in hippocampal neurons via an autophagic degradative pathway
J CELL BIOL 166, 1041-1054, 2004
Annaert W, Esselens C, Boeve C, Baert V, Snellings G, Cupers P, Craessaerts K, De Strooper B
Interaction with telencephalin and the amyloid precursor protein predicts a ring structure for presenilins
NEURON 32, 579-589, 2001
Annaert W, Levesque L, Craessaerts K, Dierynck I, Snellings G, Westaway D, St George-Hyslop P, Cordell B, Fraser P, De Strooper B
Presenilin 1 controls gamma-secretase processing of Amyloid Precursor Protein in pre-Golgi compartments of hippocampal neurons.
J CELL BIOL 147, 277-294, 1999
Search Publications
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