Spread of neuronal degeneration in a dopaminergic, Lrrk-G2019S model of Parkinson disease

Abstract

Flies expressing the most common Parkinson disease (PD)-related mutation, LRRK2-G2019S, in their dopaminergic neurons show loss of visual function and degeneration of the retina, including mitochondrial abnormalities, apoptosis and autophagy. Since the photoreceptors that degenerate are not dopaminergic, this demonstrates nonautonomous degeneration, and a spread of pathology. This provides a model consistent with Braak’s hypothesis on progressive PD. The loss of visual function is specific for the G2019S mutation, implying the cause is its increased kinase activity, and is enhanced by increased neuronal activity. These data suggest novel explanations for the variability in animal models of PD. The specificity of visual loss to G2019S, coupled with the differences in neural firing rate, provide an explanation for the variability between people with PD in visual tests.

Keywords: :

• Parkinson disease
• LRRK2
• Drosophila
• vision
• photoreceptors
• electroretinogram
• neurodegeneration
• dopaminergic neurons

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Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgment

This work was supported by Parkinson’s UK (grant number K-1007), the Wellcome Trust (grant number 097829/Z/11/A). We are grateful to Sean Sweeney for his comments on the manuscript.