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Post-translational proteomics platform identifies neurite outgrowth impairments in Parkinson's disease GBA-N370S dopamine neurons.
Bogetofte, Helle; Ryan, Brent J; Jensen, Pia; Schmidt, Sissel I; Vergoossen, Dana L E; Barnkob, Mike B; Kiani, Lisa N; Chughtai, Uroosa; Heon-Roberts, Rachel; Caiazza, Maria Claudia; McGuinness, William; Márquez-Gómez, Ricardo; Vowles, Jane; Bunn, Fiona S; Brandes, Janine; Kilfeather, Peter; Connor, Jack P; Fernandes, Hugo J R; Caffrey, Tara M; Meyer, Morten; Cowley, Sally A; Larsen, Martin R; Wade-Martins, Richard.
Affiliation
  • Bogetofte H; 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,
  • Ryan BJ; 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. Electronic address: brent.ryan@dpag.o
  • Jensen P; Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
  • Schmidt SI; 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,
  • Vergoossen DLE; Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK.
  • Barnkob MB; Centre for Cellular Immunotherapy of Haematological Cancer Odense (CITCO), Department of Clinical Immunology, Odense University Hospital, University of Southern Denmark, 5000 Odense C, Denmark.
  • Kiani LN; Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK.
  • Chughtai U; Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK.
  • Heon-Roberts R; 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.
  • Caiazza MC; 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.
  • McGuinness W; 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.
  • Márquez-Gómez R; 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.
  • Vowles J; James Martin Stem Cell Facility, Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.
  • Bunn FS; Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK.
  • Brandes J; Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK.
  • Kilfeather P; 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.
  • Connor JP; 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.
  • Fernandes HJR; 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.
  • Caffrey TM; Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK.
  • Meyer M; 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.
  • Cowley SA; James Martin Stem Cell Facility, Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.
  • Larsen MR; Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
  • Wade-Martins R; 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. Electronic address: richard.wade-mart
Cell Rep ; 42(3): 112180, 2023 03 28.
Article in En | MEDLINE | ID: mdl-36870058
ABSTRACT
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Parkinson Disease Type of study: Prognostic_studies / Risk_factors_studies Limits: Humans Language: En Journal: Cell Rep Year: 2023 Document type: Article
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Parkinson Disease Type of study: Prognostic_studies / Risk_factors_studies Limits: Humans Language: En Journal: Cell Rep Year: 2023 Document type: Article