Post-translational proteomics platform identifies neurite outgrowth impairments in Parkinson's disease GBA-N370S dopamine neurons.

Autor:	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, 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., 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.ox.ac.uk., 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, Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense C, Denmark., 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-martins@dpag.ox.ac.uk.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2023 Mar 28; Vol. 42 (3), pp. 112180. Date of Electronic Publication: 2023 Mar 03.
DOI:	10.1016/j.celrep.2023.112180
Abstrakt:	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. Competing Interests: Declaration of interests The authors’ current additional affiliations, unrelated to this work, are as follows: D.L.E.V., Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands; L.N.K., Nature Reviews Neurology, London, UK; U.C., School of Medicine, Cardiff University, Cardiff, UK; F.S.B., School of Biological Sciences, University of Edinburgh, Edinburgh, UK; J.B., Clinical Neurosciences, University of Cambridge, Cambridge, UK; J.P.C., Astbury Center for Structural Molecular Biology, School of Molecular and Cellular Biology, University of Leeds, Leeds, UK; and T.M.C., Mend the Gap, University of British Columbia, Vancouver, BC, Canada. (Copyright © 2023. Published by Elsevier Inc.)
Databáze:	MEDLINE
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