Mutations in LRRK2 cause autosomal dominant
Parkinson's disease (PD). LRRK2 encodes a multi-domain protein containing
GTPase and
kinase domains, and putative protein-protein interaction domains. Familial PD mutations alter the
GTPase and
kinase activity of LRRK2 in vitro. LRRK2 is suggested to regulate a number of cellular pathways although the underlying mechanisms are poorly understood. To explore such mechanisms, it has proved informative to identify LRRK2-interacting
proteins, some of which serve as LRRK2
kinase substrates. Here, we identify common interactions of LRRK2 with members of the
dynamin GTPase superfamily. LRRK2 interacts with
dynamin 1-3 that mediate membrane scission in
clathrin-mediated endocytosis and with
dynamin-related
proteins that mediate mitochondrial fission (Drp1) and fusion (mitofusins and OPA1). LRRK2 partially co-localizes with endosomal
dynamin-1 or with mitofusins and OPA1 at mitochondrial membranes. The subcellular distribution and oligomeric complexes of
dynamin GTPases are not altered by modulating LRRK2 in mouse brain, whereas mature OPA1 levels are reduced in G2019S PD brains. LRRK2 enhances mitofusin-1
GTP binding, whereas
dynamin-1 and OPA1 serve as modest substrates of LRRK2-mediated phosphorylation in vitro. While
dynamin GTPase orthologs are not required for LRRK2-induced toxicity in yeast, LRRK2 functionally interacts with
dynamin-1 and mitofusin-1 in cultured neurons. LRRK2 attenuates neurite shortening induced by
dynamin-1 by reducing its levels, whereas LRRK2 rescues impaired neurite outgrowth induced by mitofusin-1 potentially by reversing excessive mitochondrial fusion. Our study elucidates novel functional interactions of LRRK2 with
dynamin-superfamily
GTPases that implicate LRRK2 in the regulation of membrane dynamics important for endocytosis and mitochondrial morphology.