Anne Rovelet-Lecrux (France)
Inserm U1245
Rouen University Hospital
Anne Rovelet-Lecrux is a research engineer at the University of Rouen Normandy, France. She is working in a team leading the French National Reference Center for Early Onset Alzheimer Disease (EOAD). This unique environment enables gathering of geneticists, neurologists and fundamental biologists, thus favorizing translational research. Anne Rovelet-Lecrux has started working on Alzheimer’s disease and related dementias since her PhD, which focused on the genetic bases of neurodegenerative disorders, with a particular interest on genomic rearrangements. She then pursued her work on the genetics of dementia using pioneering genome-wide analysis methods. She mainly reported the involvement of APP duplications in EOAD, and the duplications of the MAPT gene as a novel cause of dementia. She was involved in the discovery of several genes involved in the genetic determinism of AD, including the SORL1 gene. Besides genetic analysis, she dedicates a large part of her work to the development of experimental models, using CRISPR/Cas-modified stem cells to improve the relevance of cellular models for the study of neurodegenerative disorders. The objective being a better understanding of the pathophysiological processes underpinning Alzheimer’s disease, but also to provide data regarding the causality of the variants identified in patients, allowing genetic counseling.

Presenter of 1 Presentation

 Conference Calendar

IMPAIRED SORLA MATURATION AND TRAFFICKING AS A NEW MECHANISM FOR SORL1 MISSENSE VARIANTS IN ALZHEIMER DISEASE

Session Name
0220 - GENETICS OF NEURODEGENERATION 1 (ID 7)
Session Type
SYMPOSIUM
Date
Wed, 16.03.2022
Session Time
08:30 AM - 10:30 AM
Room
ONSITE: 113
Lecture Time
09:00 AM - 09:15 AM
Presenter

Abstract

Aims

The SorLA protein, encoded by the SORL1 gene, is a major player in Alzheimer’s disease (AD) pathophysiology. Functional and genetic studies demonstrated that SorLA deficiency results in increased production of Aβ peptides, and thus a higher risk of AD. A large number of SORL1 missense variants have been identified in AD patients, but their functional consequences remain largely undefined.

Methods

In an initial screening, we overexpressed 71 SORL1 variants, identified in AD patients, in HEK293 cells to analyze the maturation profile and subcellular localization of SorLA. Five of these variations were further studied in details in CRISPR/Cas9-modified hiPSCs.

Results

Overexpression analyses revealed that 15 of the 71 SORL1 variants induced a maturation and trafficking-deficient phenotype. Validation studies on endogenous SORL1 expression in hiPSCs confirmed that maturation-defective variants were largely retained in the endoplasmic reticulum, resulting in a reduction in the delivery of SorLA to the plasma membrane and endosomal system. Importantly, this was associated with an increase of Abeta secretion, demonstrating a loss-of-function effect of these SorLA variants regarding this ultimate readout, and a direct link with AD pathophysiology. Structural analysis suggested that impaired cellular trafficking of SorLA could be due to subtle variations of the protein 3D structure resulting from changes in the interatomic interactions.

Conclusions

We here identify a new pathophysiological mechanism, by which a subset of rare SORL1 missense variants identified in AD patients induce a likely misfolded protein, thus altering the protein maturation and trafficking, and leading to a loss of the protective function of SorLA towards Abeta secretion.

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