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

Hindle SJ, Elliott CJ - Autophagy (2013)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, University of York, York, UK.

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.

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Related in: MedlinePlus

Figure 1. Flies expressing the most common PD-related mutation, Lrrk-G2019S, in their dopaminergic neurons show loss of visual response and degeneration of the retina. (A) Schematic of the experiment: G2019S or the wild-type human LRRK2 was expressed in the dopaminergic neurons (LA, MC and PPL neurons). Electrical recordings were made of the response of the photoreceptors in the eye to flashes of blue light (electroretinograms). Note that the transgene is expressed in one class of neurons, dopaminergic neurons, and the response measured in another, the histaminergic photoreceptors (arrow). (B) In young flies, the ERG trace consistently shows a sustained deflection, indicating photoreceptor activity, as long as the light is on. Old G2019S flies show a much-reduced response, showing failure of the photoreceptors. (C) The loss of function is accompanied by neurodegeneration, exemplified here by increased abundance of the autophagy marker ATG5, in the outermost layer of the photoreceptors of the G2019S flies. (Fig. modified based on those in the original publication).
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Figure 1: Figure 1. Flies expressing the most common PD-related mutation, Lrrk-G2019S, in their dopaminergic neurons show loss of visual response and degeneration of the retina. (A) Schematic of the experiment: G2019S or the wild-type human LRRK2 was expressed in the dopaminergic neurons (LA, MC and PPL neurons). Electrical recordings were made of the response of the photoreceptors in the eye to flashes of blue light (electroretinograms). Note that the transgene is expressed in one class of neurons, dopaminergic neurons, and the response measured in another, the histaminergic photoreceptors (arrow). (B) In young flies, the ERG trace consistently shows a sustained deflection, indicating photoreceptor activity, as long as the light is on. Old G2019S flies show a much-reduced response, showing failure of the photoreceptors. (C) The loss of function is accompanied by neurodegeneration, exemplified here by increased abundance of the autophagy marker ATG5, in the outermost layer of the photoreceptors of the G2019S flies. (Fig. modified based on those in the original publication).

Mentions: It was known that some people with PD had reported deficits in their sight, including contrast adaptation, and that both mammals and flies had dopaminergic neurons and receptors in their visual system. As loss of dopaminergic neurons is characteristic of PD, we therefore exposed flies to a 500-ms flash of light and recorded their response using electroretinograms (ERGs, Fig. 1A). We used the powerful GAL4-UAS system to express either the normal (wild-type) or the mutant (G2019S) form of human LRRK2, in dopaminergic neurons. Up until 10 d, both wild-type and G2019S flies respond consistently, but by 28 d the G2019S response has nearly flat-lined, while the wild-type flies still respond fully (Fig. 1B). The almost complete loss of ERG response indicates that the photoreceptors are no longer sensitive to light. The loss of photoreceptor function is accompanied by signs of degeneration throughout the visual lobes of the brain, including dilation and disorganization of the mitochondria in the G2019S photoreceptors, and stronger staining of the G2019S photoreceptors by markers of apoptosis and autophagy (Fig. 1C).


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

Hindle SJ, Elliott CJ - Autophagy (2013)

Figure 1. Flies expressing the most common PD-related mutation, Lrrk-G2019S, in their dopaminergic neurons show loss of visual response and degeneration of the retina. (A) Schematic of the experiment: G2019S or the wild-type human LRRK2 was expressed in the dopaminergic neurons (LA, MC and PPL neurons). Electrical recordings were made of the response of the photoreceptors in the eye to flashes of blue light (electroretinograms). Note that the transgene is expressed in one class of neurons, dopaminergic neurons, and the response measured in another, the histaminergic photoreceptors (arrow). (B) In young flies, the ERG trace consistently shows a sustained deflection, indicating photoreceptor activity, as long as the light is on. Old G2019S flies show a much-reduced response, showing failure of the photoreceptors. (C) The loss of function is accompanied by neurodegeneration, exemplified here by increased abundance of the autophagy marker ATG5, in the outermost layer of the photoreceptors of the G2019S flies. (Fig. modified based on those in the original publication).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3672307&req=5

Figure 1: Figure 1. Flies expressing the most common PD-related mutation, Lrrk-G2019S, in their dopaminergic neurons show loss of visual response and degeneration of the retina. (A) Schematic of the experiment: G2019S or the wild-type human LRRK2 was expressed in the dopaminergic neurons (LA, MC and PPL neurons). Electrical recordings were made of the response of the photoreceptors in the eye to flashes of blue light (electroretinograms). Note that the transgene is expressed in one class of neurons, dopaminergic neurons, and the response measured in another, the histaminergic photoreceptors (arrow). (B) In young flies, the ERG trace consistently shows a sustained deflection, indicating photoreceptor activity, as long as the light is on. Old G2019S flies show a much-reduced response, showing failure of the photoreceptors. (C) The loss of function is accompanied by neurodegeneration, exemplified here by increased abundance of the autophagy marker ATG5, in the outermost layer of the photoreceptors of the G2019S flies. (Fig. modified based on those in the original publication).
Mentions: It was known that some people with PD had reported deficits in their sight, including contrast adaptation, and that both mammals and flies had dopaminergic neurons and receptors in their visual system. As loss of dopaminergic neurons is characteristic of PD, we therefore exposed flies to a 500-ms flash of light and recorded their response using electroretinograms (ERGs, Fig. 1A). We used the powerful GAL4-UAS system to express either the normal (wild-type) or the mutant (G2019S) form of human LRRK2, in dopaminergic neurons. Up until 10 d, both wild-type and G2019S flies respond consistently, but by 28 d the G2019S response has nearly flat-lined, while the wild-type flies still respond fully (Fig. 1B). The almost complete loss of ERG response indicates that the photoreceptors are no longer sensitive to light. The loss of photoreceptor function is accompanied by signs of degeneration throughout the visual lobes of the brain, including dilation and disorganization of the mitochondria in the G2019S photoreceptors, and stronger staining of the G2019S photoreceptors by markers of apoptosis and autophagy (Fig. 1C).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, University of York, York, UK.

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.

Show MeSH
Related in: MedlinePlus