SorLA Protective Function Is Restored by Improving SorLA Protein Maturation in a Subset of Alzheimer’s Disease-Associated SORL1 Missense Variants

Article type: Short Communication

Authors: Miguel, Laetitia | Gervais, Juliette | Nicolas, Gaël | Lecourtois, Magalie^{; *}

Affiliations: Univ Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Genetics and CNR-MAJ, F-76000 Rouen, France

Correspondence: [*] Correspondence to: Magalie Lecourtois, Inserm U1245, Faculty of Medicine, 22 Boulevard Gambetta, 76183 Rouen Cedex, France. Tel: +33 2 3514 8304; E-mail: magalie.lecourtois@univ-rouen.fr.

Abstract: SORL1 loss of function is associated with Alzheimer’s disease (AD) risk through increased Aβ peptide secretion. We expressed 10 maturation-defective rare missense SORL1 variants in HEK cells and showed that decreasing growing temperature led to a significant increase in the maturation of the encoded protein SorLA for 6/10. In edited hiPSC carrying two of these variants, maturation of the protein was restored partially by decreasing the culture temperature and was associated with concomitant decrease in Aβ secretion. Correcting SorLA maturation in the context of maturation-defective missense variants could thus be a relevant strategy to improve SorLA protective function against AD.

Keywords: Alzheimer’s disease, amyloid, CRISPR-Cas Systems, induced pluripotent stem cells, missense mutations, SORL1, temperature

DOI: 10.3233/JAD-230211

Journal: Journal of Alzheimer's Disease, vol. 94, no. 4, pp. 1343-1349, 2023