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Functional interaction of Parkinsons disease-associated LRRK2 with members of the dynamin GTPase superfamily
- Source :
- Human Molecular Genetics
- Publisher :
- Oxford University Press
-
Abstract
- 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.
- Subjects :
- endocrine system
Blotting, Western
Saccharomyces cerevisiae
Protein Serine-Threonine Kinases
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
Mitochondrial Membrane Transport Proteins
GTP Phosphohydrolases
Immunoenzyme Techniques
Rats, Sprague-Dawley
Dynamin II
Mice
Neuroblastoma
Two-Hybrid System Techniques
Neurites
Animals
Humans
Immunoprecipitation
Protein Interaction Domains and Motifs
Phosphorylation
Cells, Cultured
Dynamin I
Mice, Knockout
Neurons
Parkinson Disease
Articles
Endocytosis
Rats
nervous system diseases
HEK293 Cells
Case-Control Studies
Mitochondrial Membranes
Mutation
Female
Dynamin III
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Human Molecular Genetics
- Accession number :
- edsair.pmid.dedup....515df1ce8901bbbdac2b698b849afc5d