Impaired SorLA maturation and trafficking as a new mechanism for SORL1 missense variants in Alzheimer disease

Anne Rovelet-Lecrux (1, 2) , Sebastien Feuillette (1, 2) , Laetitia Miguel (1, 2) , Catherine Schramm (1, 2) , Ségolène Pernet (1, 2) , Olivier Quenez (1, 2) , Isabelle Ségalas-Milazzo (3) , Laure Guilhaudis (3) , Stéphane Rousseau (1, 2) , Gaëtan Riou (4) , Thierry Frébourg (1, 2) , Dominique Campion (1, 2) , Gaël Nicolas (1, 2) , Magalie Lecourtois (1, 2)

1 GPMCND - Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques
2 CHU Rouen
3 COBRA - Chimie Organique et Bioorganique : Réactivité et Analyse
4 PANTHER - Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices

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. Here, we identified a new pathophysiological mechanism, by which rare SORL1 missense variants identified in AD patients result in altered maturation and trafficking of the SorLA protein. An initial screening, based on the overexpression of 70 SorLA variants in HEK293 cells, revealed that 15 of them (S114R, R332W, G543E, S564G, S577P, R654W, R729W, D806N, Y934C, D1535N, D1545E, P1654L, Y1816C, W1862C, P1914S) induced a maturation and trafficking-deficient phenotype. Three of these variants (R332W, S577P, and R654W) and two maturation-competent variants (S124R and N371T) were further studied in details in CRISPR/Cas9-modified hiPSCs. When expressed at endogenous levels, the R332W, S577P, and R654W SorLA variants also showed a maturation defective profile. We further demonstrated that these variants were largely retained in the endoplasmic reticulum, resulting in a reduction in the delivery of SorLA mature protein to the plasma membrane and to the endosomal system. Importantly, expression of the R332W and R654W variants in hiPSCs was associated with a clear increase of Aβ secretion, demonstrating a loss-of-function effect of these SorLA variants regarding this ultimate readout, and a direct link with AD pathophysiology. Furthermore, structural analysis of the impact of missense variants on SorLA protein suggested that impaired cellular trafficking of SorLA protein could be due to subtle variations of the protein 3D structure resulting from changes in the interatomic interactions.

Mots clés: SorLA; iPSC; Alzheimer's disease; Maturation defects; Trafficking

Domaines: Biochimie, Biologie Moléculaire; Biologie cellulaire; Génétique; Médecine humaine et pathologie

Anne Rovelet-Lecrux, Sebastien Feuillette, Laetitia Miguel, Catherine Schramm, Ségolène Pernet, et al.. Impaired SorLA maturation and trafficking as a new mechanism for SORL1 missense variants in Alzheimer disease. Acta Neuropathologica Communications, 2021, 9, ⟨10.1186/s40478-021-01294-4⟩. ⟨hal-03512083⟩