LRRK2 regulates retrograde synaptic compensation at the Drosophila neuromuscular junction

Parkinson's disease gene leucine-rich repeat kinase 2 (LRRK2) has been implicated in a number of processes including the regulation of mitochondrial function, autophagy and endocytic dynamics; nevertheless, we know little about its potential role in the regulation of synaptic plasticity. Here we demonstrate that postsynaptic knockdown of the fly homologue of LRRK2 thwarts retrograde, homeostatic synaptic compensation at the larval neuromuscular junction. Conversely, postsynaptic overexpression of either the fly or human LRRK2 transgene induces a retrograde enhancement of presynaptic neurotransmitter release by increasing the size of the release ready pool of vesicles. We show that LRRK2 promotes cap-dependent translation and identify Furin 1 as its translational target, which is required for the synaptic function of LRRK2. As the regulation of synaptic homeostasis plays a fundamental role in ensuring normal and stable synaptic function, our findings suggest that aberrant function of LRRK2 may lead to destabilization of neural circuits.

(d) Quantification of the number of active zones per NMJ from the genotypes shown in (a). n = 10, 10.
(f) Quantification of the fluorescent intensity of GluRIIC staining from the genotypes in (c). n = 15 for each.
(i) Quantification of the average number of T-bars per active zone from the genotypes shown in (e, f). n = 55 w1118 and 191 dLrrk synapse profiles. Error Bars are SEM.

Electrophysiology data
Tukey (T) or Games-Howell (GH) post-hoc test was applied after one-way ANOVA. T test was applied for all pairwise comparison.

Data for Figure 1b
Genotype