LRRK2 regulates dendritic spine dynamics through interaction with post-synaptic actin cytoskeleton

Dendritic spines, small protrusions of the dendrites, constitute the postsynaptic compartment of excitatory synapses. Filamentous actin is the major cytoskeletal constituent of dendritic spines, whose dynamic nature allows them to plastically remodel their shape and volume in response to stimuli. Notably, dendritic spine abnormalities are linked to a number of neurological and neurodegenerative disorders. Here, we show that the Parkinson disease (PD)-associated kinase LRRK2 participates in spine remodeling processing by binding a panel of actin-related proteins enriched in postsynaptic compartments. Phosphorylation of LRRK2 Ser935, which controls LRRK2 subcellular localization, rapidly increases upon brain-derived neurotrophic factor (BDNF) stimulation of differentiated SH-SY5Y cells and primary mouse neurons. Affinity-purification coupled with mass spectrometry (AP-MS/MS) analysis revealed that LRRK2 interactome is significantly reshaped upon BDNF stimulation, with an interconnected network of actin cytoskeleton-associated proteins increasing their binding to LRRK2. Accordingly, Lrrk2 knockout primary neurons exhibit impaired response to BDNF-induced spinogenesis and TrkB signaling. In vivo, one-month old Lrrk2 knockout mice exhibit defects in spine maturation, a phenotype that disappears with age. Finally, by comparing the phosphoproteomes of Lrrk2 wild-type versus Lrrk2 G2019S PD mutant synaptosomes, we found that the differentially phosphorylated proteins are enriched in categories related to postsynaptic structural organization. Taken together, our study discloses a critical function of LRRK2 in shaping dendritic spine morphology during development and defines a mechanistic role of the kinase in postsynaptic actin-cytoskeletal dynamics. ### Competing Interest Statement The authors have declared no competing interest.