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

Humans Dopaminergic Neurons / metabolism Glucosylceramidase / genetics Mutation Neuronal Outgrowth Parkinson Disease / genetics Protein Processing, Post-Translational Proteomics
CP: Neuroscience Parkinson’s glucocerebrosidase glycosylation iPSC lysosome neuritogenesis phosphoproteomics post-translational modifications proteomics stem cells

Journal

Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691

Informations de publication

Date de publication:
28 03 2023
Historique:
received: 29 07 2021
revised: 04 10 2022
accepted: 13 02 2023
medline: 3 4 2023
pubmed: 5 3 2023
entrez: 4 3 2023
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.celrep.2023.112180 PMID: 36870058
pubmed: 36870058
pii: S2211-1247(23)00191-2
doi: 10.1016/j.celrep.2023.112180
pii:
doi:

Substances chimiques

Glucosylceramidase EC 3.2.1.45
GBA protein, human EC 3.2.1.45

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

112180

Subventions

Organisme : Medical Research Council
ID : MR/P007058/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N029453/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/M024962/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_EX_MR/N50192X/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L023784/2
Pays : United Kingdom
Organisme : Wellcome Trust
ID : WTISSF121302
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N013255/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 090532/Z/09/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0900747 91070
Pays : United Kingdom

Informations de copyright

Copyright © 2023. Published by Elsevier Inc.

Déclaration de conflit d'intérêts

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.

Auteurs

Helle 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.

Brent J 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.

Pia Jensen (P)

Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.

Sissel I 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.

Dana L E Vergoossen (DLE)

Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK.

Mike B 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.

Lisa N Kiani (LN)

Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK.

Uroosa Chughtai (U)

Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK.

Rachel 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.

Maria Claudia 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.

William 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.

Ricardo 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.

Jane Vowles (J)

James Martin Stem Cell Facility, Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.

Fiona S Bunn (FS)

Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK.

Janine Brandes (J)

Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK.

Peter 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.

Jack P 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.

Hugo J R 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.

Tara M Caffrey (TM)

Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK.

Morten 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.

Sally A Cowley (SA)

James Martin Stem Cell Facility, Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.

Martin R Larsen (MR)

Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.

Richard 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.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Post-translational proteomics platform...
questionsmedicales.fr › Cellules › Neurones › Neurones dopaminergiques › Post-translational proteomics platform...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Hydrolases › Glycosidases › Glucosidases › Glucosylceramidase › Post-translational proteomics platform...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Post-translational proteomics platform...
questionsmedicales.fr › Phénomènes physiologiques de l'appareil locomoteur et du système nerveux › Phénomènes physiologiques du système nerveux › Neurogenèse › Excroissance neuronale › Post-translational proteomics platform...
questionsmedicales.fr › Maladies du système nerveux › Maladies neurodégénératives › Maladie de Parkinson › Post-translational proteomics platform...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Modification traductionnelle des protéines › Maturation post-traductionnelle des protéines › Post-translational proteomics platform...
questionsmedicales.fr › Disciplines des sciences naturelles › Chimie › Biochimie › Protéomique › Post-translational proteomics platform...