NGLY1 mutations cause protein aggregation in human neurons

Andreea Manole, Thomas Wong, Amanda Rhee, Sammy Novak, Shao Ming Chin, Katya Tsimring, Andres Paucar, April Williams, Traci Fang Newmeyer, Simon T. Schafer, Idan Rosh, Susmita Kaushik, Rene Hoffman, Songjie Chen, Guangwen Wang, Michael Snyder, Ana Maria Cuervo, Leo Andrade, Uri Manor, Kevin LeeJeffrey R. Jones, Shani Stern, Maria C. Marchetto, Fred H. Gage

Research output: Contribution to journalArticlepeer-review


Biallelic mutations in the gene that encodes the enzyme N-glycanase 1 (NGLY1) cause a rare disease with multi-symptomatic features including developmental delay, intellectual disability, neuropathy, and seizures. NGLY1’s activity in human neural cells is currently not well understood. To understand how NGLY1 gene loss leads to the specific phenotypes of NGLY1 deficiency, we employed direct conversion of NGLY1 patient-derived induced pluripotent stem cells (iPSCs) to functional cortical neurons. Transcriptomic, proteomic, and functional studies of iPSC-derived neurons lacking NGLY1 function revealed several major cellular processes that were altered, including protein aggregate-clearing functionality, mitochondrial homeostasis, and synaptic dysfunctions. These phenotypes were rescued by introduction of a functional NGLY1 gene and were observed in iPSC-derived mature neurons but not astrocytes. Finally, laser capture microscopy followed by mass spectrometry provided detailed characterization of the composition of protein aggregates specific to NGLY1-deficient neurons. Future studies will harness this knowledge for therapeutic development.

Original languageEnglish
Article number113466
JournalCell Reports
Issue number12
StatePublished - 26 Dec 2023

Bibliographical note

Publisher Copyright:
© 2023 The Authors


  • CP: Neuroscience
  • NGLY1 deficiency
  • chaperones
  • fragmented mitochondria
  • neural cells
  • organoids
  • protein aggregates

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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