NGLY1 mutations cause protein aggregation in human neurons

• DOI: 10.1016/j.celrep.2023.113466
• Publication Date: 2023-11-30T12:12:31Z
• Authors: 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 Lee; Jeffrey R. Jones; Shani Stern; Maria C. Marchetto; Fred H. Gage
• Keywords: Proteomics; Neurons; QH301-705.5; neural cells; protein aggregates; Article; Mitochondria; Protein Aggregates; CP: Neuroscience; Mutation; chaperones; Humans; Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase; fragmented mitochondria; Biology (General); NGLY1 deficiency; organoids

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.