title: The small GTPase Rab11 co-localizes with α-synuclein in intracellular inclusions and modulates its aggregation, secretion and toxicity.
abstract: Alpha-synuclein (aSyn) misfolding and aggregation are pathological features common to several neurodegenerative diseases, including Parkinson's disease (PD). Mounting evidence suggests that aSyn can be secreted and transferred from cell to cell, participating in the propagation and spreading of pathological events. Rab11, a small GTPase, is an important regulator in both endocytic and secretory pathways. Here, we show that Rab11 is involved in regulating aSyn secretion. Rab11 knockdown or overexpression of either Rab11a wild-type (Rab11a WT) or Rab11a GDP-bound mutant (Rab11a S25N) increased secretion of aSyn. Furthermore, we demonstrate that Rab11 interacts with aSyn and is present in intracellular inclusions together with aSyn. Moreover, Rab11 reduces aSyn aggregation and toxicity. Our results suggest that Rab11 is involved in modulating the processes of aSyn secretion and aggregation, both of which are important mechanisms in the progression of aSyn pathology in PD and other synucleinopathies.
authors.affiliation: Cell and Molecular Neuroscience Unit, Instituto de Medicina Molecular, Lisbon, Portugal.
authors.forename: Oldriska
authors.initials: O
authors.lastname: Chutna
authors.affiliation: Cell and Molecular Neuroscience Unit, Instituto de Medicina Molecular, Lisbon, Portugal.
authors.forename: Susana
authors.initials: S
authors.lastname: Gonçalves
authors.affiliation: Department of Neurodegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Villar-Piqué
authors.affiliation: Cell and Molecular Neuroscience Unit, Instituto de Medicina Molecular, Lisbon, Portugal Department of Neurodegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Patrícia
authors.initials: P
authors.lastname: Guerreiro
authors.affiliation: Cell and Molecular Neuroscience Unit, Instituto de Medicina Molecular, Lisbon, Portugal.
authors.forename: Zrinka
authors.initials: Z
authors.lastname: Marijanovic
authors.affiliation: Cell and Molecular Neuroscience Unit, Instituto de Medicina Molecular, Lisbon, Portugal.
authors.forename: Tiago
authors.initials: T
authors.lastname: Mendes
authors.affiliation: CEDOC, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal.
authors.forename: José
authors.initials: J
authors.lastname: Ramalho
authors.affiliation: Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
authors.forename: Evangelia
authors.initials: E
authors.lastname: Emmanouilidou
authors.affiliation: Institut de Biotecnologia i Biomedicina Departament de Bioquimica i Biologia Molecular, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.
authors.forename: Salvador
authors.initials: S
authors.lastname: Ventura
authors.affiliation: Department of Molecular Neurology, University Hospital, Erlangen, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Klucken
authors.affiliation: CEDOC, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal.
authors.forename: Duarte C
authors.initials: DC
authors.lastname: Barral
authors.affiliation: Department of Genetics, University of Leicester, University Road, Leicester, UK and.
authors.forename: Flaviano
authors.initials: F
authors.lastname: Giorgini
authors.affiliation: Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
authors.forename: Kostas
authors.initials: K
authors.lastname: Vekrellis
authors.affiliation: Cell and Molecular Neuroscience Unit, Instituto de Medicina Molecular, Lisbon, Portugal Department of Neurodegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, Göttingen, Germany Instituto de Fisiologia, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal tiago.outeiro@med.uni-goettingen.de.
authors.forename: Tiago F
authors.initials: TF
authors.lastname: Outeiro
mesh_terms: D001692:Biological Transport; D045744:Cell Line, Tumor; D055354:Exosomes / Q000737:chemistry / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D002479:Inclusion Bodies / Q000737:chemistry* / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010957:Plasmids / Q000737:chemistry / Q000378:metabolism; D066329:Protein Aggregates / Q000235:genetics; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000099193:rab11 GTP-Binding Proteins
chemical_list: D066329:Protein Aggregates; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D051844:alpha-Synuclein; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins