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

Cell Rep. 2021 Jun 15;35(11):109259. doi: 10.1016/j.celrep.2021.109259.


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.

Keywords: Alzheimer's disease; SORL1; amyloid precursor protein; autophagy; endosome; iPSC; lysosome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Protein Precursor / metabolism*
  • Aspartic Acid Endopeptidases / metabolism
  • Autophagy*
  • Dementia / genetics
  • Dementia / pathology
  • Endosomes / metabolism*
  • Gene Knockout Techniques
  • Humans
  • Induced Pluripotent Stem Cells / metabolism
  • LDL-Receptor Related Proteins / deficiency*
  • LDL-Receptor Related Proteins / genetics
  • LDL-Receptor Related Proteins / metabolism
  • Lysosomes / metabolism*
  • Membrane Transport Proteins / deficiency*
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism
  • Neurons / metabolism*
  • Oligonucleotides, Antisense / administration & dosage
  • Oligonucleotides, Antisense / pharmacology
  • Phenotype
  • Protein Binding


  • Amyloid beta-Protein Precursor
  • LDL-Receptor Related Proteins
  • Membrane Transport Proteins
  • Oligonucleotides, Antisense
  • SORL1 protein, human
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human