Oxford Parkinson’s Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Dorothy Crowfoot Hodgkin Building, South Parks Road, Oxford OX1 3QU, UK; Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense C, Denmark; Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark
Brent J. Ryan
Oxford Parkinson’s Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Dorothy Crowfoot Hodgkin Building, South Parks Road, Oxford OX1 3QU, UK; Corresponding author
Pia Jensen
Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark
Sissel I. Schmidt
Oxford Parkinson’s Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Dorothy Crowfoot Hodgkin Building, South Parks Road, Oxford OX1 3QU, UK; Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense C, Denmark
Dana L.E. Vergoossen
Oxford Parkinson’s Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK
Mike B. Barnkob
Centre for Cellular Immunotherapy of Haematological Cancer Odense (CITCO), Department of Clinical Immunology, Odense University Hospital, University of Southern Denmark, 5000 Odense C, Denmark
Lisa N. Kiani
Oxford Parkinson’s Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK
Uroosa Chughtai
Oxford Parkinson’s Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK
Rachel Heon-Roberts
Oxford Parkinson’s Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Dorothy Crowfoot Hodgkin Building, South Parks Road, Oxford OX1 3QU, UK
Maria Claudia Caiazza
Oxford Parkinson’s Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Dorothy Crowfoot Hodgkin Building, South Parks Road, Oxford OX1 3QU, UK
William McGuinness
Oxford Parkinson’s Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Dorothy Crowfoot Hodgkin Building, South Parks Road, Oxford OX1 3QU, UK
Ricardo Márquez-Gómez
Oxford Parkinson’s Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Dorothy Crowfoot Hodgkin Building, South Parks Road, Oxford OX1 3QU, UK
Jane Vowles
James Martin Stem Cell Facility, Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK
Fiona S. Bunn
Oxford Parkinson’s Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK
Janine Brandes
Oxford Parkinson’s Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK
Peter Kilfeather
Oxford Parkinson’s Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Dorothy Crowfoot Hodgkin Building, South Parks Road, Oxford OX1 3QU, UK
Jack P. Connor
Oxford Parkinson’s Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Dorothy Crowfoot Hodgkin Building, South Parks Road, Oxford OX1 3QU, UK
Hugo J.R. Fernandes
Oxford Parkinson’s Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Dorothy Crowfoot Hodgkin Building, South Parks Road, Oxford OX1 3QU, UK
Tara M. Caffrey
Oxford Parkinson’s Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK
Morten Meyer
Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense C, Denmark; Department of Neurology, Odense University Hospital, 5000 Odense C, Denmark
Sally A. Cowley
James Martin Stem Cell Facility, Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK
Martin R. Larsen
Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark
Richard Wade-Martins
Oxford Parkinson’s Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Dorothy Crowfoot Hodgkin Building, South Parks Road, Oxford OX1 3QU, UK; Corresponding author
Summary: Variants at the GBA locus, encoding glucocerebrosidase, are the strongest common genetic risk factor for Parkinson’s disease (PD). To understand GBA-related disease mechanisms, we use a multi-part-enrichment proteomics and post-translational modification (PTM) workflow, identifying large numbers of dysregulated proteins and PTMs in heterozygous GBA-N370S PD patient induced pluripotent stem cell (iPSC) dopamine neurons. Alterations in glycosylation status show disturbances in the autophagy-lysosomal pathway, which concur with upstream perturbations in mammalian target of rapamycin (mTOR) activation in GBA-PD neurons. Several native and modified proteins encoded by PD-associated genes are dysregulated in GBA-PD neurons. Integrated pathway analysis reveals impaired neuritogenesis in GBA-PD neurons and identify tau as a key pathway mediator. Functional assays confirm neurite outgrowth deficits and identify impaired mitochondrial movement in GBA-PD neurons. Furthermore, pharmacological rescue of glucocerebrosidase activity in GBA-PD neurons improves the neurite outgrowth deficit. Overall, this study demonstrates the potential of PTMomics to elucidate neurodegeneration-associated pathways and potential drug targets in complex disease models.
