Neural and metabolic dysregulation in PMM2-deficient human in vitro neural models
Silvia Radenkovic,
Rohit Budhraja,
Teun Klein-Gunnewiek,
Alexia Tyler King,
Tarun N. Bhatia,
Anna N. Ligezka,
Karen Driesen,
Rameen Shah,
Bart Ghesquière,
Akhilesh Pandey,
Nael Nadif Kasri,
Steven A. Sloan,
Eva Morava,
Tamas Kozicz
Affiliations
Silvia Radenkovic
Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA
Rohit Budhraja
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA
Teun Klein-Gunnewiek
Department of Human Genetics, Radboud University Medical Centre, 6525 XZ Nijmegen, the Netherlands
Alexia Tyler King
Department of Human Genetics, Emory University, Atlanta, GA 30322, USA
Tarun N. Bhatia
Department of Human Genetics, Emory University, Atlanta, GA 30322, USA
Anna N. Ligezka
Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA
Karen Driesen
Metabolomics Expertise Center, VIB-KU Leuven, 3000 Leuven, Belgium
Rameen Shah
Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
Bart Ghesquière
Metabolomics Expertise Center, VIB-KU Leuven, 3000 Leuven, Belgium; Laboratory of Applied Mass Spectrometry, KU Leuven, 3000 Leuven, Belgium
Akhilesh Pandey
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA; Manipal Academy of Higher Education (MAHE), Manipal, Karnataka 576104, India
Nael Nadif Kasri
Department of Human Genetics, Radboud University Medical Centre, 6525 XZ Nijmegen, the Netherlands
Steven A. Sloan
Department of Human Genetics, Emory University, Atlanta, GA 30322, USA
Eva Morava
Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA; Department of Biophysics, University of Pécs Medical School, 7624 Pécs, Hungary; Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York City, NY 10029, USA
Tamas Kozicz
Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA; Department of Anatomy, University of Pécs Medical School, 7624 Pécs, Hungary; Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York City, NY 10029, USA; Corresponding author
Summary: Phosphomannomutase 2-congenital disorder of glycosylation (PMM2-CDG) is a rare inborn error of metabolism caused by deficiency of the PMM2 enzyme, which leads to impaired protein glycosylation. While the disorder presents with primarily neurological symptoms, there is limited knowledge about the specific brain-related changes caused by PMM2 deficiency. Here, we demonstrate aberrant neural activity in 2D neuronal networks from PMM2-CDG individuals. Utilizing multi-omics datasets from 3D human cortical organoids (hCOs) derived from PMM2-CDG individuals, we identify widespread decreases in protein glycosylation, highlighting impaired glycosylation as a key pathological feature of PMM2-CDG, as well as impaired mitochondrial structure and abnormal glucose metabolism in PMM2-deficient hCOs, indicating disturbances in energy metabolism. Correlation between PMM2 enzymatic activity in hCOs and symptom severity suggests that the level of PMM2 enzyme function directly influences neurological manifestations. These findings enhance our understanding of specific brain-related perturbations associated with PMM2-CDG, offering insights into the underlying mechanisms and potential directions for therapeutic interventions.
