SORL1 deficiency in human excitatory neurons causes APP-dependent defects in the endolysosome-autophagy network
Year: 2021
Type: article
Abstract: 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.
Source: Cell Reports
Institutions: University College London, University of Cambridge, The Gurdon Institute, Amsterdam Neuroscience, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam UMC Location Vrije Universiteit Amsterdam, Delft University of Technology, Hong Kong University of Science and Technology, UK Dementia Research Institute, UCL Queen Square Institute of Neurology
Language: English
Subfield: Physiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,200
Funders: Wellcome Trust, EU Joint Programme – Neurodegenerative Disease Research, Health~Holland, Alzheimer's Society, National Institute for Health and Care Research, Parkinson's UK, University College London, European Commission, Rosetrees Trust, ZonMw, Alzheimer’s Research UK, UK Dementia Research Institute, Medical Research Council, UCLH Biomedical Research Centre, NIHR Great Ormond Street Hospital Biomedical Research Centre
Awards: G1090293845, UK Dementias Platform, G1798618210, Using genetic variability in whole transcriptome expression in cells and tissues to understand the pathogenesis of Parkinson's and Alzheimer's disease, G2501976640, G2852415654, G3327757157, G4315210197, BRAINEACv2: a resource for the interpretation of genetic variation in multiple regions of the adult human brain, G4985110482, Understanding the genes for Parkinson's disease, Risk and Modifying factors in Fronto Temporal Dementia, G6323016957, BRAINEACv2: a resource for the interpretation of genetic variation in multiple regions of the adult human brain, G7979393549, G807055969, Using Next Generation Sequencing to Unravel the Pathogenesis of Sporadic Inclusion Body Myositis - The International IBM Consortium Genetic Study, G8832252702, G975443604
OpenAlex ID: W3169527058