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

Abstract

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.

Penetrance estimation of Alzheimer disease in SORL1 loss-of-function variant carriers using a family-based strategy and stratification by APOE genotypes

“…Here, we used stringent criteria to restrict our analysis to a set of variants with homogeneous effect (PTV + Mis3-LoF), in accordance with our simulation study. Indeed, since Mis3 variants were defined solely through bioinformatics prediction tools in case-control studies, we can expect that there is some diversity of the variant effects on the encoded SorLA protein function towards Aβ secretion [ 33 ], so that our estimates may not be directly translated to all Mis3 SORL1 variants. Moreover, the penetrance curves reflect well the penetrance associated with one SORL1 -LoF variant and may not predict what is expected for a carrier of bi-allelic SORL1 -LoF variants.…”

A Patient with Corticobasal Syndrome and Progressive Non-Fluent Aphasia (CBS-PNFA), with Variants in ATP7B, SETX, SORL1, and FOXP1 Genes

“…The V118M variant detected in our patient localized between two previously characterized mutations S114R and S124R in SORLA protein [ 76 ]. The S124R mutation showed a maturation profile similar to the wild-type protein, and the S114R mutation led to the decreased production of a mature, glycosylated form of the protein, which resulted in inefficient transport to the cell membrane [ 76 ]. It is thus plausible that also V118M variant may affect maturation defects and cellular localization of SORLA since position 118 in the protein is strongly conserved (phyloP100way).…”

“…A recent functional study revealed that many SORL1 rare variants resulted in altered maturation and cellular trafficking of the SORLA protein [ 76 ]. The V118M variant detected in our patient localized between two previously characterized mutations S114R and S124R in SORLA protein [ 76 ].…”

“…A recent functional study revealed that many SORL1 rare variants resulted in altered maturation and cellular trafficking of the SORLA protein [ 76 ]. The V118M variant detected in our patient localized between two previously characterized mutations S114R and S124R in SORLA protein [ 76 ]. The S124R mutation showed a maturation profile similar to the wild-type protein, and the S114R mutation led to the decreased production of a mature, glycosylated form of the protein, which resulted in inefficient transport to the cell membrane [ 76 ].…”

Comprehensive analysis of next-generation sequencing data in COVID-19 and its secondary complications

“…Pathways include immune system [83], adaptive immune system [84], neutrophil degranulation [85], cytokine signaling in immune system [86] and GPCR ligand binding [87] were responsible for progression of COVID-19 infection. A previous study demonstrated that the expression levels of AHSP (alpha hemoglobin stabilizing protein) [ [105], ATM (ATM serine/threonine kinase) [106], CD28 [107], LRRK2 [108], CCL5 [109], CD33 [110], FCRL3 [111], CCR3 [112], FGL2 [113], GZMA (granzyme A) [114], PICALM (phosphatidylinositol binding clathrin assembly protein) [115], ALOX5 [116], MME (membrane metalloendopeptidase) [117], VIM (vimentin) [118], CD93 [119], GCA (grancalcin) [120], CD226 [121] RASGRP1 [130], TLR2 [131], DOCK2 [132], CSF1R [133], PRKCB (protein kinase C beta) [134], CAMK4 [135], CXCL5 [136], CD36 [137], P2RY12 [138], LILRB2 [139], CD5 [140], SLC25A37 [141], ADIPOR1 [142], PECAM1 [143], RGS10 [144], RGS18 [145], ANK1 [146], RNF182 [147], NPRL3 [148], NINJ2 [149], KCNA3 [150], ABCG2 [151], MS4A6A [152], WDR45 [153], RAB39B [154], SORL1 [155], LRRN3 [156], DPM2 [157], SLC4A10…”