Abstract:
:LRRK2 is a kinase mutated in Parkinson's disease, but how the protein affects synaptic function remains enigmatic. We identified LRRK2 as a critical regulator of EndophilinA. Using genetic and biochemical studies involving Lrrk loss-of-function mutants and Parkinson-related LRRK2(G2019S) gain-of-kinase function, we show that LRRK2 affects synaptic endocytosis by phosphorylating EndoA at S75, a residue in the BAR domain. We show that LRRK2-mediated EndoA phosphorylation has profound effects on EndoA-dependent membrane tubulation and membrane association in vitro and in vivo and on synaptic vesicle endocytosis at Drosophila neuromuscular junctions in vivo. Our work uncovers a regulatory mechanism that indicates that reduced LRRK2 kinase activity facilitates EndoA membrane association, while increased kinase activity inhibits membrane association. Consequently, both too much and too little LRRK2-dependent EndoA phosphorylation impedes synaptic endocytosis, and we propose a model in which LRRK2 kinase activity is part of an EndoA phosphorylation cycle that facilitates efficient vesicle formation at synapses.
journal_name
Neuronjournal_title
Neuronauthors
Matta S,Van Kolen K,da Cunha R,van den Bogaart G,Mandemakers W,Miskiewicz K,De Bock PJ,Morais VA,Vilain S,Haddad D,Delbroek L,Swerts J,Chávez-Gutiérrez L,Esposito G,Daneels G,Karran E,Holt M,Gevaert K,Moechars DW,Dedoi
10.1016/j.neuron.2012.08.022subject
Has Abstractpub_date
2012-09-20 00:00:00pages
1008-21issue
6eissn
0896-6273issn
1097-4199pii
S0896-6273(12)00759-3journal_volume
75pub_type
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