SORL1 deficiency in human excitatory neurons causes APP-dependent defects in the endolysosome-autophagy network
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...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2021-06-01
|
| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124721006239 |
| _version_ | 1818891934367744000 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Christy Hung |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-19T17:48:42Z |
| format | Article |
| id | doaj.art-2806293dc8bf440ca1a2cd951d19946a |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-19T17:48:42Z |
| publishDate | 2021-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-2806293dc8bf440ca1a2cd951d19946a2022-12-21T20:11:59ZengElsevierCell Reports2211-12472021-06-013511109259SORL1 deficiency in human excitatory neurons causes APP-dependent defects in the endolysosome-autophagy networkChristy Hung0Eleanor Tuck1Victoria Stubbs2Sven J. van der Lee3Cora Aalfs4Resie van Spaendonk5Philip Scheltens6John Hardy7Henne Holstege8Frederick J. Livesey9UCL Great Ormond Street Institute of Child Health, Zayed Centre for Research into Rare Disease in Children, 20 Guilford Street, London WC1N 1DZ, UKUCL Great Ormond Street Institute of Child Health, Zayed Centre for Research into Rare Disease in Children, 20 Guilford Street, London WC1N 1DZ, UKGurdon Institute, University of Cambridge, Cambridge CB2 1QN, UKAlzheimer 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 NetherlandsDepartment of Clinical Genetics, Amsterdam UMC, Amsterdam, the NetherlandsDepartment of Clinical Genetics, Amsterdam UMC, Amsterdam, the NetherlandsAlzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the NetherlandsUK 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, ChinaAlzheimer 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 NetherlandsUCL Great Ormond Street Institute of Child Health, Zayed Centre for Research into Rare Disease in Children, 20 Guilford Street, London WC1N 1DZ, UK; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124721006239endosomelysosomeautophagyAlzheimer's diseaseamyloid precursor proteinSORL1 |
| spellingShingle | 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 SORL1 deficiency in human excitatory neurons causes APP-dependent defects in the endolysosome-autophagy network Cell Reports endosome lysosome autophagy Alzheimer's disease amyloid precursor protein SORL1 |
| title | SORL1 deficiency in human excitatory neurons causes APP-dependent defects in the endolysosome-autophagy network |
| title_full | SORL1 deficiency in human excitatory neurons causes APP-dependent defects in the endolysosome-autophagy network |
| title_fullStr | SORL1 deficiency in human excitatory neurons causes APP-dependent defects in the endolysosome-autophagy network |
| title_full_unstemmed | SORL1 deficiency in human excitatory neurons causes APP-dependent defects in the endolysosome-autophagy network |
| title_short | SORL1 deficiency in human excitatory neurons causes APP-dependent defects in the endolysosome-autophagy network |
| title_sort | sorl1 deficiency in human excitatory neurons causes app dependent defects in the endolysosome autophagy network |
| topic | endosome lysosome autophagy Alzheimer's disease amyloid precursor protein SORL1 |
| url | http://www.sciencedirect.com/science/article/pii/S2211124721006239 |
| work_keys_str_mv | AT christyhung sorl1deficiencyinhumanexcitatoryneuronscausesappdependentdefectsintheendolysosomeautophagynetwork AT eleanortuck sorl1deficiencyinhumanexcitatoryneuronscausesappdependentdefectsintheendolysosomeautophagynetwork AT victoriastubbs sorl1deficiencyinhumanexcitatoryneuronscausesappdependentdefectsintheendolysosomeautophagynetwork AT svenjvanderlee sorl1deficiencyinhumanexcitatoryneuronscausesappdependentdefectsintheendolysosomeautophagynetwork AT coraaalfs sorl1deficiencyinhumanexcitatoryneuronscausesappdependentdefectsintheendolysosomeautophagynetwork AT resievanspaendonk sorl1deficiencyinhumanexcitatoryneuronscausesappdependentdefectsintheendolysosomeautophagynetwork AT philipscheltens sorl1deficiencyinhumanexcitatoryneuronscausesappdependentdefectsintheendolysosomeautophagynetwork AT johnhardy sorl1deficiencyinhumanexcitatoryneuronscausesappdependentdefectsintheendolysosomeautophagynetwork AT henneholstege sorl1deficiencyinhumanexcitatoryneuronscausesappdependentdefectsintheendolysosomeautophagynetwork AT frederickjlivesey sorl1deficiencyinhumanexcitatoryneuronscausesappdependentdefectsintheendolysosomeautophagynetwork |