Lucía Chávez-Gutiérrez Lab

Research focus

Genetics has shown that mutations in functionally related genes (Presenilins (PSEN) and Amyloid Precursor Protein (APP)) cause Alzheimer’s disease (AD) with early onset. PSEN is the catalytic subunit of the γ-secretase intramembrane proteases, which sequentially cleave APP to generate Aβ peptides. Alzheimer’s disease-causing mutations consistently lead to production of longer amyloidogenic Aβ peptides and this points at the shift in Aβ length as fundamental to the disease pathogenic mechanism. The mutant-induced changes in Aβ profiles as well as the Aβ-mediated neurotoxicity mechanism are poorly defined. 

We are interested in generating a quantitative understanding of the molecular mechanisms underlying Alzheimer’s disease pathogenicity. Our research is based on the premise that getting a better mechanistic understanding of the function of the molecules involved in familial Alzheimer’s disease (FAD) will offer critical insights into the molecular basis of the disease and open new research avenues leading to innovative and safe strategies to tackle the disease in the clinic. 

Our studies have revealed that pathogenic mutations in PSEN and APP destabilize γ-secretase-APP/Aβn (Enzyme-Substrate) complexes, promoting their dissociation and thereby the release of longer Aβ peptides from APP (Szaruga et al., 2017 in Cell). These findings provide substantial insights into the mechanisms underlying γ-secretase dysfunction in Alzheimer’s disease and support a novel unifying model for Alzheimer’s causative mutations that places generation of longer Aβ peptides central to disease pathogenesis. Significantly, our findings suggest that environmental factors targeting the stabilities of the γ-secretase-APP/Aβn complexes may affect Alzheimer’s risk.

In support of this idea, our direct quantifications of γ-secretase activity and processivity in post-mortem brain samples of sporadic AD (SAD) patients identified a sub-group of SAD patient samples displaying “FAD-like” γ-secretase alterations (impaired γ-secretase processivity) (Szaruga et al., 2015). 

Our interest extends to the study of the relationships between function and structure that govern γ-secretase proteolysis. Our previous studies depict γ-secretase as a dynamic ensemble of distinct conformational states, which equilibrium is “remodelled” by protease inhibition or the presence of a familial AD-linked PSEN mutations (Elad et al., 2015). We use Nanobodies as conformational probes to investigate the conformational landscape of these complex proteases.​​​​

Publications

Extracellular interface between APP and Nicastrin regulates Aß length and response to gamma-secretase modulators.Petit Dieter Hitzenberger Manuel Lismont Sam Zoltowska Katarzyna Marta Ryan Natalie Mercken Marc Bischoff François Zacharias Martin Chávez-Gutiérrez Lucía@EMBO JOURNAL, 38, e101494, 2019@ These authors are corresponding.
Alzheimer's-Causing Mutations Shift Abeta Length by Destabilizing gamma-Secretase-Abetan InteractionsSzaruga M Munteanu B Lismont S Veugelen S Horré K Mercken M Saido T Ryan N De Vos T Savvides S Gallardo R Schymkowitz J Rousseau F Fox N Hopf C De Strooper B* Chávez Gutiérrez L*CELL, 170, 443-456 e14, 2017* These authors contributed equally
Familial Alzheimer's Disease Mutations in Presenilin Generate Amyloidogenic Abeta Peptide SeedsVeugelen S Saito T Saido T Chávez Gutiérrez L* De Strooper B*NEURON, 90, 410-6, 2016* These authors contributed equally
Qualitative changes in human gamma-secretase underlie familial Alzheimer's diseaseSzaruga M* Veugelen S* Benurwar M Lismont S Sepulveda-Falla D Lleo A Ryan N Lashley T Fox N Murayama S Gijsen H De Strooper B Chávez Gutiérrez LJOURNAL OF EXPERIMENTAL MEDICINE, 212, 2003-13, 2015* These authors contributed equally
The dynamic conformational landscape of gamma-secretase NadavElad Nadav De Strooper Bart Lismont Sam Hagen W Veugelen Sarah Arimon M Horré Katrien Berezovska O Sachse C Chávez Gutiérrez LucíaJOURNAL OF CELL SCIENCE, 128, 589-98, 2015

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News

9 VIB researchers received funding from the Alzheimer Foundation

21/03/2019 - VIB is very grateful to the Alzheimer Research Foundation for funding the researchers received, which helps them in their quest for cures. The ​Foundation has been fighting Alzheimer's disease for years and is working on a future without dementia.

Lucía Chávez Gutiérrez

Lucía Chávez Gutiérrez

Research area(s)

Model organism(s)

Bio

PhD: Natl. Univ. of México, Mexico, 2005
Postdoc: VIB-KU Leuven, Leuven, Belgium, 2005-10
Assistant Professor: KU Leuven, Leuven, Belgium, since 2013
VIB Group leader since July 2017

Contact Info

VIB-KU Leuven Center for Brain & Disease ResearchO&N 4, 6e verdCampus GasthuisbergHerestraat 49, bus 602 3000 LEUVENRoute description