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Investigating the Role of LRRK2 in the Visual System in a Drosophila Model of Parkinson's Disease

Furmston, Rebecca (2016) Investigating the Role of LRRK2 in the Visual System in a Drosophila Model of Parkinson's Disease. PhD thesis, University of York.

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Abstract

The kinase domain LRRK2-G2019S mutation is the most common cause of familial Parkinson’s disease (PD). Some PD patients report visual defects, which may originate through the loss of dopaminergic (DA) signalling in the retina. Since Drosophila, like mammals, have retinal DA neurons, the in vivo role of dLRRK/LRRK2 was examined genetically and by using potential therapeutic compounds to treat PD. Here, it was shown that old dLRRK¯ loss-of-function flies have a deficit in signalling in the visual neurons, though photoreception is unaffected. This deficit is rescued with expression of dLRRK, hLRRK2 or mLRRK1 in the DA neurons, but also with dLRRK expression in the non-dopaminergic lamina neurons, photoreceptors or glial cells, suggesting a role of extra-synaptic cell-cell signalling. Placing the dLRRK¯ mutation in a white-eyed background proved to be lethal. In the gain-of-function assay, old flies with DA expression of LRRK2-G2019S show a second kind of visual defect, reduced photoreception, indicating cell-cell signalling of LRRK2. Feeding these flies with mitochondrial rescue agents or a kinase inhibitor substantially improves the visual response; the vision of control flies is unaffected. Additionally, white-eyed flies with DA expression of LRRK2-G2019S do not show the neurodegeneration seen in red-eyed flies. Since the mammalian kidney secretes LRRK2 in exosomes, our data may be interpreted by an exosome mediated transfer of LRRK2 between neurons, photoreceptor and glia. Lysosomes are linked to the production of the red/brown pigment granules in the fly eye, as well as to exosomes. As fly pigment granules, like melanosomes, are lysosomal-related organelles, our data provide an explanation for the high sensitivity of DA neurons in PD. Finally, our data suggest novel therapies could result from drugs targeting the eye pigments or through using mitochondrial rescue agents.

Item Type: Thesis (PhD)
Related URLs:
Academic Units: The University of York > Biology (York)
Depositing User: Miss Rebecca Furmston
Date Deposited: 13 Jan 2017 10:42
Last Modified: 13 Jan 2017 10:42
URI: http://etheses.whiterose.ac.uk/id/eprint/15849

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