SORL1 deficiency in human excitatory neurons causes APP-dependent defects in the endolysosome-autophagy network
Christy Hung,
Eleanor Tuck,
Victoria Stubbs,
Sven J. van der Lee,
Cora Aalfs,
Resie van Spaendonk,
Philip Scheltens,
John Hardy,
Henne Holstege,
Frederick J. Livesey
Affiliations
Christy Hung
UCL Great Ormond Street Institute of Child Health, Zayed Centre for Research into Rare Disease in Children, 20 Guilford Street, London WC1N 1DZ, UK
Eleanor Tuck
UCL Great Ormond Street Institute of Child Health, Zayed Centre for Research into Rare Disease in Children, 20 Guilford Street, London WC1N 1DZ, UK
Victoria Stubbs
Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK
Sven J. van der Lee
Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands; Department of Clinical Genetics, Amsterdam UMC, Amsterdam, the Netherlands; Delft Bioinformatics Lab, Delft University of Technology, Delft, the Netherlands
Cora Aalfs
Department of Clinical Genetics, Amsterdam UMC, Amsterdam, the Netherlands
Resie van Spaendonk
Department of Clinical Genetics, Amsterdam UMC, Amsterdam, the Netherlands
Philip Scheltens
Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands
John Hardy
UK Dementia Research Institute and Department of Neurodegenerative Disease and Reta Lila Weston Institute, UCL Queen Square Institute of Neurology and UCL Movement Disorders Centre, University College London, London, UK; Institute for Advanced Study, The Hong Kong University of Science and Technology, Hong Kong, China
Henne Holstege
Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands; Department of Clinical Genetics, Amsterdam UMC, Amsterdam, the Netherlands; Delft Bioinformatics Lab, Delft University of Technology, Delft, the Netherlands
Frederick J. Livesey
UCL Great Ormond Street Institute of Child Health, Zayed Centre for Research into Rare Disease in Children, 20 Guilford Street, London WC1N 1DZ, UK; Corresponding author
Summary: Dysfunction 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.
