Journal
HUMAN MOLECULAR GENETICS
Volume 26, Issue 15, Pages 2933-2948Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddx179
Keywords
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Funding
- JSPS in Japan [16K09679, 26860219, 26293070, 15H04842]
- MEXT in Japan [23111003]
- Otsuka Pharmaceutical
- Grants-in-Aid for Scientific Research [15H04842, 26293070, 17K08522, 16K09679, 17H04049, 26860219] Funding Source: KAKEN
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Mutations of the retromer component Vps35 and endosomal kinase LRRK2 are linked to autosomal dominant forms of familial Parkinson's disease (PD). However, the physiological and pathological roles of Vps35 and LRRK2 in neuronal functions are poorly understood. Here, we demonstrated that the loss of Drosophila Vps35 (dVps35) affects synaptic vesicle recycling, dopaminergic synaptic release and sleep behavior associated with dopaminergic activity, which is rescued by the expression of wild-type dVps35 but not the PD-associated mutant dVps35 D647N. Drosophila LRRK2 dLRRK together with Rab5 and Rab11 is also implicated in synaptic vesicle recycling, and the manipulation of these activities improves the Vps35 synaptic phenotypes. These findings indicate that defects of synaptic vesicle recycling in which two late-onset PD genes, Vps35 and LRRK2, are involved could be key aspects of PD etiology.
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