A Drosophila model for LRRK2 -linked parkinsonism

Abstract

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

R1441C mutation in LRRK2 impairs dopaminergic neurotransmission in mice

“…Interestingly, Tg flies expressing either human WT or mutant G2019S LRRK2 exhibit selective loss of DA neurons, locomotor dysfunction, and early mortality (19), whereas Tg expression of WT or pathogenic equivalent mutant forms of LRRK, the sole Drosophila ortholog of human LRRK2, does not result in any significant defects in flies (18). However, it is unclear why expression of human LRRK2 or fly LRRK has such different effects in flies, and why expression of either WT or mutant human LRRK2 similarly results in loss of DA neurons in flies.…”

“…Recently, Lee et al (18) reported that loss-of-function mutants for LRRK, the sole Drosophila ortholog of human LRRK2, exhibited severely impaired locomotor activity and reduced tyrosine hydroxylase (TH) immunoreactivity in DA neurons, but transgenic (Tg) expression of pathogenic mutant or WT LRRK did not result in any significant defects. However, in another study, Tg expression of human WT or G2019S LRRK2 led to adult-onset selective loss of DA neurons, locomotor dysfunction, and early mortality in Drosophila (19).…”

Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications

“…Transgenic expression of human G2019S LRRK2 in Drosophila causes dendrite degeneration and dopaminergic (DA) neurons loss followed by locomotor dysfunction [114,115]. Importantly, this effect was diminished by pharmacological inhibition of kinase activity of G2019S mutant or by overexpression of parkin, a protein implicated in autosomalrecessive Parkinsonism [116,117].…”

Update on the Functional Biology of Lrrk2

“…Overexpression of dLRRKWT or Roc domain substitution R1069C (comparable to Lrrk2 R1441C in humans) using a number of different GAL4 drivers (directed to muscle, whole-body and dopaminergic neurons) produced no deleterious effects [75]. The effects of overexpression of human WT and G2019S Lrrk2 were investigated using GAL4 drivers for the photoreceptor cells (gmr-GAL4) or in dopaminergic neurons (ddc-GAL4) [77]. Progressive retinal degeneration was observed in gmr-GAL4 WT and G2019S flies similar to that shown in other fly neurodegeneration models.…”