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 Lee,
Jeffrey R. Jones,
Shani Stern,
Maria C. Marchetto,
Fred H. Gage
Affiliations
Andreea Manole
Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA
Thomas Wong
Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA
Amanda Rhee
Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA
Sammy Novak
Waitt Advanced Biophotonics Core, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
Shao-Ming Chin
Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA
Katya Tsimring
Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA
Andres Paucar
Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA
April Williams
The Razavi Newman Integrative Genomics and Bioinformatics Core Facility, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
Traci Fang Newmeyer
Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA
Simon T. Schafer
Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA
Idan Rosh
Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel
Susmita Kaushik
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY 10461, USA
Rene Hoffman
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
Songjie Chen
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
Guangwen Wang
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
Michael Snyder
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
Ana Maria Cuervo
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY 10461, USA
Leo Andrade
Waitt Advanced Biophotonics Core, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
Uri Manor
Waitt Advanced Biophotonics Core, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
Kevin Lee
Grace Science Foundation, Menlo Park, CA 94025, USA
Jeffrey R. Jones
Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA
Shani Stern
Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel
Maria C. Marchetto
Department of Anthropology, University of California, San Diego, La Jolla, CA 92093, USA
Fred H. Gage
Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA; Corresponding author
Summary: 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.
