SORL1 deficiency in human excitatory neurons causes APP-dependent defects in the endolysosome-autophagy network.

Christy Hung,Frederick J Livesey,Sven J Van Der Lee,Cora Aalfs,Eleanor Tuck,John Hardy,Victoria Stubbs,Resie Van Spaendonk,Henne Holstege,Philip Scheltens

doi:10.1016/j.celrep.2021.109259

Abstract

SummaryDysfunction of the endolysosomal-autophagy network is emerging as an important pathogenic process in Alzheimer’s disease. Mutations in the sorting receptor-encoding gene SORL1 cause autosomal-dominant Alzheimer’s disease, and SORL1 variants increase risk for late-onset AD. To understand the contribution of SORL1 mutations to AD pathogenesis, we analyze the effects of a SORL1 truncating mutation on SORL1 protein levels and endolysosome function in human neurons. We find that truncating mutation results in SORL1 haploinsufficiency and enlarged endosomes in human neurons. Analysis of isogenic SORL1 wild-type, heterozygous, and homozygous null neurons demonstrates that, whereas SORL1 haploinsufficiency results in endosome dysfunction, complete loss of SORL1 leads to additional defects in lysosome function and autophagy. Neuronal endolysosomal dysfunction caused by loss of SORL1 is relieved by extracellular antisense oligonucleotide-mediated reduction of APP protein, demonstrating that PSEN1, APP, and SORL1 act in a common pathway regulating the endolysosome system, which becomes dysfunctional in AD.

Highlights

Dysfunction of the endolysosome-autophagy network is an early pathological feature of Alzheimer’s disease (AD) (Nixon, 2017) and is emerging as an important pathogenic process in the monogenic, inherited form of the disease (Hung and Livesey, 2018; Kwart et al, 2019)
Enlarged endosomes in neurons generated from an individual with dementia as a result of a truncating SORL1 mutation To understand how SORL1 truncating variants may impact the onset and progression of AD, we generated cortical excitatory neurons from induced pluripotent stem cells derived from an individual clinically diagnosed with AD and carrying a truncating SORL1 mutation at exon 20 (Figure 1A), who was homozygous for the APOE4 allele, which independently increases the risk for AD by approximately 12-fold (Kim et al, 2009)
In neurons generated from the patient-derived induced pluripotent stem cells (iPSCs), full-length SORL1 protein levels were at ~50% of those detected in a non-demented control (Figure 1C)

Summary

Introduction

Dysfunction of the endolysosome-autophagy network is an early pathological feature of Alzheimer’s disease (AD) (Nixon, 2017) and is emerging as an important pathogenic process in the monogenic, inherited form of the disease (Hung and Livesey, 2018; Kwart et al, 2019). Converging lines of evidence from studies in cell culture (Rogaeva et al, 2007), knockout (KO) mouse models (Caglayan et al, 2014; Dodson et al, 2008), and individuals with AD indicate that loss of SORL1 function (i.e., haploinsufficiency) is a cause of monogenic AD, in addition to autosomal dominant missense mutations in APP, PSEN1, and PSEN2 (Sager et al, 2007; Scherzer et al, 2004) Both stop-gain and frameshift mutations in SORL1 are exclusively observed in AD patients (Holstege et al, 2017; Raghavan et al, 2018), providing direct genetic evidence that truncating variants of SORL1 are highly penetrant.

Results

Discussion

Conclusion