title: Rab11 modulates α-synuclein-mediated defects in synaptic transmission and behaviour.
abstract: A central pathological hallmark of Parkinson's disease (PD) is the presence of proteinaceous depositions known as Lewy bodies, which consist largely of the protein α-synuclein (aSyn). Mutations, multiplications and polymorphisms in the gene encoding aSyn are associated with familial forms of PD and susceptibility to idiopathic PD. Alterations in aSyn impair neuronal vesicle formation/transport, and likely contribute to PD pathogenesis by neuronal dysfunction and degeneration. aSyn is functionally associated with several Rab family GTPases, which perform various roles in vesicle trafficking. Here, we explore the role of the endosomal recycling factor Rab11 in the pathogenesis of PD using Drosophila models of aSyn toxicity. We find that aSyn induces synaptic potentiation at the larval neuromuscular junction by increasing synaptic vesicle (SV) size, and that these alterations are reversed by Rab11 overexpression. Furthermore, Rab11 decreases aSyn aggregation and ameliorates several aSyn-dependent phenotypes in both larvae and adult fruit flies, including locomotor activity, degeneration of dopaminergic neurons and shortened lifespan. This work emphasizes the importance of Rab11 in the modulation of SV size and consequent enhancement of synaptic function. Our results suggest that targeting Rab11 activity could have a therapeutic value in PD.
authors.affiliation: Department of Genetics, University of Leicester, University Road, Leicester LE1 7RH, UK.
authors.forename: Carlo
authors.initials: C
authors.lastname: Breda
authors.affiliation: Department of Genetics, University of Leicester, University Road, Leicester LE1 7RH, UK, MRC Toxicology Unit, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: Marie L
authors.initials: ML
authors.lastname: Nugent
authors.affiliation: Department of Genetics, University of Leicester, University Road, Leicester LE1 7RH, UK.
authors.forename: Jasper G
authors.initials: JG
authors.lastname: Estranero
authors.affiliation: Department of Genetics, University of Leicester, University Road, Leicester LE1 7RH, UK.
authors.forename: Charalambos P
authors.initials: CP
authors.lastname: Kyriacou
authors.affiliation: Department of NeuroDegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Goettingen, Göttingen, Germany and Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Tiago F
authors.initials: TF
authors.lastname: Outeiro
authors.affiliation: MRC Toxicology Unit, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: Joern R
authors.initials: JR
authors.lastname: Steinert
authors.affiliation: Department of Genetics, University of Leicester, University Road, Leicester LE1 7RH, UK, fg36@le.ac.uk.
authors.forename: Flaviano
authors.initials: F
authors.lastname: Giorgini
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism / Q000473:pathology; D059290:Dopaminergic Neurons / Q000378:metabolism; D004330:Drosophila; D005260:Female; D015870:Gene Expression; D008954:Models, Biological; D009469:Neuromuscular Junction / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism; D010641:Phenotype; D021381:Protein Transport; D009435:Synaptic Transmission; D013572:Synaptic Vesicles / Q000378:metabolism / Q000648:ultrastructure; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000378:metabolism*; D000099193:rab11 GTP-Binding Proteins
chemical_list: D051844:alpha-Synuclein; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins