Cell Reports (Mar 2023)
Post-translational proteomics platform identifies neurite outgrowth impairments in Parkinson’s disease GBA-N370S dopamine neurons
- Helle Bogetofte,
- Brent J. Ryan,
- Pia Jensen,
- Sissel I. Schmidt,
- Dana L.E. Vergoossen,
- Mike B. Barnkob,
- Lisa N. Kiani,
- Uroosa Chughtai,
- Rachel Heon-Roberts,
- Maria Claudia Caiazza,
- William McGuinness,
- Ricardo Márquez-Gómez,
- Jane Vowles,
- Fiona S. Bunn,
- Janine Brandes,
- Peter Kilfeather,
- Jack P. Connor,
- Hugo J.R. Fernandes,
- Tara M. Caffrey,
- Morten Meyer,
- Sally A. Cowley,
- Martin R. Larsen,
- Richard Wade-Martins
Affiliations
- Helle Bogetofte
- 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
- Journal volume & issue
-
Vol. 42,
no. 3
p. 112180
Abstract
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.
