Rab11 modulates α-synuclein-mediated defects in synaptic transmission and behaviour

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...

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Bibliographic Details
Published in:Human molecular genetics 2015-02, Vol.24 (4), p.1077-1091
Main Authors: Breda, Carlo, Nugent, Marie L, Estranero, Jasper G, Kyriacou, Charalambos P, Outeiro, Tiago F, Steinert, Joern R, Giorgini, Flaviano
Format: Article
Language:English
Subjects:
alpha-Synuclein - genetics
alpha-Synuclein - metabolism
Animals
Behavior, Animal
Brain - metabolism
Brain - pathology
Dopaminergic Neurons - metabolism
Drosophila
Female
Gene Expression
Models, Biological
Neuromuscular Junction - metabolism
Parkinson Disease - metabolism
Phenotype
Protein Transport
rab GTP-Binding Proteins - metabolism
Synaptic Transmission
Synaptic Vesicles - metabolism
Synaptic Vesicles - ultrastructure
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Summary: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.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/ddu521