Targeted kinase inhibition relieves slowness and tremor in a Drosophila model of LRRK2 Parkinson\u2019s disease

Amy C Cording,Christopher J H Elliott,Laurence G Wilson,Nicolas Shiaelis,C Adam Middleton,Stavroula Petridi

doi:10.1038/s41531-017-0036-y

Amy C Cording, Christopher J H Elliott + Show 4 more

Open Access

https://doi.org/10.1038/s41531-017-0036-y

Copy DOI

Journal: npj Parkinson's Disease	Publication Date: Dec 1, 2017
Citations: 18	License type: open-access

Affiliation: University of York

Abstract

In a number of Drosophila models of genetic Parkinson’s disease (PD) flies climb more slowly than wild-type controls. However, this assay does not distinguish effects of PD-related genes on gravity sensation, “arousal”, central pattern generation of leg movements, or muscle. To address this problem, we have developed an assay for the fly proboscis extension response (PER). This is attractive because the PER has a simple, well-identified reflex neural circuit, in which sucrose sensing neurons activate a pair of “command interneurons”, and thence motoneurons whose activity contracts the proboscis muscle. This circuit is modulated by a single dopaminergic neuron (TH-VUM). We find that expressing either the G2019S or I2020T (but not R1441C, or kinase dead) forms of human LRRK2 in dopaminergic neurons reduces the percentage of flies that initially respond to sucrose stimulation. This is rescued fully by feeding l-DOPA and partially by feeding kinase inhibitors, targeted to LRRK2 (LRRK2-IN-1 and BMPPB-32). High-speed video shows that G2019S expression in dopaminergic neurons slows the speed of proboscis extension, makes its duration more variable, and increases the tremor. Testing subsets of dopaminergic neurons suggests that the single TH-VUM neuron is likely most important in this phenotype. We conclude the Drosophila PER provides an excellent model of LRRK2 motor deficits showing bradykinesia, akinesia, hypokinesia, and increased tremor, with the possibility to localize changes in neural signaling.

Highlights

Parkinson’s disease (PD) is a progressive neurodegenerative condition characterized by pathological loss of dopaminergic neurons in the substantia nigra
We have found that expression of LRRK2-G2019S, the most common cause of genetic PD, in dopamine neurons results in a reduced proboscis extension response (PER), with bradykinesia, akinesia, and tremor, and that this is rescued by L-DOPA or by kinase inhibitors targeted at LRRK2
LRRK2-G2019S mutation, with its increased kinase activity, a Upregulation of LRRK2 kinase activity in dopaminergic neurons causes akinesia In order to test the neuronal specificity of the PD-related mutation LRRK2-G2019S, we first expressed this in each of the components promising therapy would be to deploy kinase inhibitors targeted at LRRK2

Summary

Introduction

Parkinson’s disease (PD) is a progressive neurodegenerative condition characterized by pathological loss of dopaminergic neurons in the substantia nigra. The excellent genetic toolkit provided by Drosophila led to the creation of fly models of PD These reflect many features of the disease PDmimic flies have reduced movement, it is hard to specify exactly where the changes are taking place (response to the startle stimulus or gravity, or effects on the central pattern generator or motor neurons or changes directly affecting the leg muscles themselves). This assay fails to discriminate between the different possible movement defects (akinesia, hypokinesia, and bradykinesia).

Methods

Results

Conclusion