Mutations in the leucine-rich repeat kinase (LRRK2) gene cause lateonset autosomal dominant Parkinson's disease (PD) with pleiomorphic pathology. Previously, we and others found that expression of mutant LRRK2 causes neuronal degeneration in cell culture. Here we used the GAL4/UAS system to generate transgenic Drosophila expressing either wild-type human LRRK2 or LRRK2-G2019S, the most common mutation associated with PD. Expression of either wild-type human LRRK2 or LRRK2-G2019S in the photoreceptor cells caused retinal degeneration. Expression of LRRK2 or LRRK2-G2019S in neurons produced adult-onset selective loss of dopaminergic neurons, locomotor dysfunction, and early mortality. Expression of mutant G2019S-LRRK2 caused a more severe parkinsonism-like phenotype than expression of equivalent levels of wild-type LRRK2. Treatment with L-DOPA improved mutant LRRK2-induced locomotor impairment but did not prevent the loss of tyrosine hydroxylase-positive neurons. To our knowledge, this is the first in vivo''gain-of-function'' model which recapitulates several key features of LRRK2-linked human parkinsonism. These flies may provide a useful model for studying LRRK2-linked pathogenesis and for future therapeutic screens for PD intervention.dopaminergic neuron ͉ Parkinson's disease

Summary The mechanisms by which the fruitfly, Drosophila melanogaster, detect sweet compounds are poorly understood; however, a subset of the family of 68 gustatory receptors (Grs) has emerged as the key receptors. These seven transmembrane receptors include Gr5a and at least one member of the six genes in the Gr64 cluster (Gr64a), which are expressed in sugar-responsive neurons. Disruption of Gr5a prevents the detection of trehalose [1–3], while mutation of Gr64a impairs the responses to sucrose, maltose and glucose [4, 5]. Recent studies suggest that these sugar receptors may require a co-receptor for function in vivo [4–6]; however, the identity of the putative co-receptor is not known. In the current work, we demonstrate that Gr64f is required in combination with Gr5a for the behavioral response to trehalose and for production of action potentials due to application of trehalose. Gr64f was also required in concert with Gr64a to rescue the defects in the sensitivities to sucrose, maltose and glucose, resulting from deletion of the entire Gr64 cluster. These data suggest that Drosophila sugar receptors function as multimers and that Gr64f is required broadly as a co-receptor for the detection of sugars.

Motor coordination is broadly divided into gross and fine motor control, both of which depend on proprioceptive organs. However, the channels that function specifically in fine motor control are unknown. Here, we show that mutations in trpγ disrupt fine motor control while leaving gross motor proficiency intact. The mutants are unable to coordinate precise leg movements during walking, and are ineffective in traversing large gaps due to an inability in making subtle postural adaptations that are requisite for this task. TRPγ is expressed in proprioceptive organs, and is required in both neurons and glia for gap crossing. We expressed TRPγ in vitro, and found that its activity is promoted by membrane stretch. A mutation eliminating the Na+/Ca2+ exchanger suppresses the gap crossing phenotype of trpγ flies. Our findings indicate that TRPγ contributes to fine motor control through mechanical activation in proprioceptive organs, thereby promoting Ca2+ influx, which is required for function.