Contrast Acuity With Different Colors in Parkinson's Disease

Gupta, Harish; Zhang, Nan; Driver‐Dunckley, Erika; Mehta, Shyamal H.; Beach, Thomas G.; Adler, Charles H.

doi:10.1002/mdc3.12821

Cited by 6 publications

(3 citation statements)

References 27 publications

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“…In People with Parkinson's, the retinal degeneration of dopaminergic amacrine cells is accompanied by changes in contrast detection e.g. [38]. We therefore tested if the anatomical degeneration of the fly eye is linked to a loss of visual physiological contrast sensitivity.…”

Section: Dopaminergic Reduction In Rab10 Rescues G2019s-induced Visual Deficitsmentioning

confidence: 99%

Multiple Pathways of LRRK2-G2019S/Rab10 Interaction in Dopaminergic Neurons

Fellgett

Middleton

Munns

et al. 2021

JPD

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Background: Inherited mutations in the LRRK2 protein are the common causes of Parkinson’s disease, but the mechanisms by which increased kinase activity of mutant LRRK2 leads to pathological events remain to be determined. In vitro assays (heterologous cell culture, phospho-protein mass spectrometry) suggest that several Rab proteins might be directly phosphorylated by LRRK2-G2019S. An in vivo screen of Rab expression in dopaminergic neurons in young adult Drosophila demonstrated a strong genetic interaction between LRRK2-G2019S and Rab10. Objective: To determine if Rab10 is necessary for LRRK2-induced pathophysiological responses in the neurons that control movement, vision, circadian activity, and memory. These four systems were chosen because they are modulated by dopaminergic neurons in both humans and flies. Methods: LRRK2-G2019S was expressed in Drosophila dopaminergic neurons and the effects of Rab10 depletion on Proboscis Extension, retinal neurophysiology, circadian activity pattern (‘sleep’), and courtship memory determined in aged flies. Results: Rab10 loss-of-function rescued LRRK2-G2019S induced bradykinesia and retinal signaling deficits. Rab10 knock-down, however, did not rescue the marked sleep phenotype which results from dopaminergic LRRK2-G2019S. Courtship memory is not affected by LRRK2, but is markedly improved by Rab10 depletion. Anatomically, both LRRK2-G2019S and Rab10 are seen in the cytoplasm and at the synaptic endings of dopaminergic neurons. Conclusion: We conclude that, in Drosophila dopaminergic neurons, Rab10 is involved in some, but not all, LRRK2-induced behavioral deficits. Therefore, variations in Rab expression may contribute to susceptibility of different dopaminergic nuclei to neurodegeneration seen in people with Parkinson’s disease.

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Section: Dopaminergic Reduction In Rab10 Rescues G2019s-induced Visual Deficitsmentioning

confidence: 99%

Multiple Pathways of LRRK2-G2019S/Rab10 Interaction in Dopaminergic Neurons

Fellgett

Middleton

Munns

et al. 2021

JPD

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“…Notably, the early stage of PD seems to be characterized by defects in color vision and contrast sensitivity, with a color discrimination deficit worsening with disease severity [88,92].…”

Section: Signs Of Visual Dysfunction In Parkinson's Diseasementioning

confidence: 99%

Retinal Alterations Predict Early Prodromal Signs of Neurodegenerative Disease

Casciano,

Zauli,

Celeghini

et al. 2024

IJMS

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Neurodegenerative diseases are an increasingly common group of diseases that occur late in life with a significant impact on personal, family, and economic life. Among these, Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the major disorders that lead to mild to severe cognitive and physical impairment and dementia. Interestingly, those diseases may show onset of prodromal symptoms early after middle age. Commonly, the evaluation of these neurodegenerative diseases is based on the detection of biomarkers, where functional and structural magnetic resonance imaging (MRI) have shown a central role in revealing early or prodromal phases, although it can be expensive, time-consuming, and not always available. The aforementioned diseases have a common impact on the visual system due to the pathophysiological mechanisms shared between the eye and the brain. In Parkinson’s disease, α-synuclein deposition in the retinal cells, as well as in dopaminergic neurons of the substantia nigra, alters the visual cortex and retinal function, resulting in modifications to the visual field. Similarly, the visual cortex is modified by the neurofibrillary tangles and neuritic amyloid β plaques typically seen in the Alzheimer’s disease brain, and this may reflect the accumulation of these biomarkers in the retina during the early stages of the disease, as seen in postmortem retinas of AD patients. In this light, the ophthalmic evaluation of retinal neurodegeneration could become a cost-effective method for the early diagnosis of those diseases, overcoming the limitations of functional and structural imaging of the deep brain. This analysis is commonly used in ophthalmic practice, and interest in it has risen in recent years. This review will discuss the relationship between Alzheimer’s disease and Parkinson’s disease with retinal degeneration, highlighting how retinal analysis may represent a noninvasive and straightforward method for the early diagnosis of these neurodegenerative diseases.

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“…People with Parkinson's also show visual deficits including loss of dopaminergic neurons from the retina [30,31], which affect contrast perception, e.g. [32]. Aged THG2 flies also show strong retinal degeneration which occurs more quickly when the flies are subjected to a mild visual stress [15].…”

Section: Dopaminergic Reduction In Rab10 Rescues G2019s-induced Visuamentioning

confidence: 99%

Multiple pathways of LRRK2-G2019S / Rab10 interaction in dopaminergic neurons

Fellgett

Middleton

Munns

et al. 2020

Preprint

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BackgroundInherited mutations in the LRRK2 protein are the most common known cause of Parkinson’s, but the mechanisms by which increased kinase activity of mutant LRRK2 leads to pathological events remain to be determined. In vitro assays (heterologous cell culture, phospho-protein mass spectrometry) suggest that several Rab proteins might be directly phosphorylated by LRRK2-G2019S. Which Rabs interact with LRRK2 in dopaminergic neurons to facilitate normal and pathological physiological responses remains to be determined. An in vivo screen of Rab expression in dopaminergic neurons in young adult Drosophila demonstrated a strong genetic interaction between LRRK2-G2019S and Rab10. We now ask if Rab10 is required for LRRK2-induced physiological responses in DA neurons.MethodsLRRK2-G2019S was expressed in Drosophila dopaminergic neurons and the effects of Rab10 depletion on Proboscis Extension, vision, circadian activity pattern and courtship memory determined in aged flies.ResultsRab10 loss-of-function rescued bradykinesia of the Proboscis Extension Response (PER) and visual defects of aged flies expressing LRRK2-G2019S in DA neurons. Rab10 knock-down however, did not rescue the marked sleep phenotype which results from dopaminergic expression of LRRK2-G2019S. Courtship memory is not affected by LRRK2 expression, but is markedly improved by Rab10 depletion. Anatomically, both LRRK2-G2019S and Rab10 are seen in the cytoplasm and at the synaptic endings of dopaminergic neurons.ConclusionsWe conclude that, in Drosophila dopaminergic neurons, Rab10 is involved differentially in LRRK2-induced behavioral deficits. Therefore, variations in Rab expression may contribute to susceptibility of dopaminergic neurons to neurodegeneration seen in people with Parkinson’s.Graphical AbstractRab10 depletion ameliorates the proboscis extension bradykinesia and loss of synaptic signalling in the retina induced by LRRK2-G2019S expression (magenta arrows/orange crosses). Rab10 manipulation does not affect the ‘sleep’ phenotype from LRRK2-G2019S (magenta arrow). Reduction of Rab10 facilitates conditioned courtship memory, but LRRK2 has no effect (yellow arrow). All manipulations of Rab10 and G2019S in dopaminergic neurons, shown in the outline of the brain (filled cells have high levels of Rab10). We conclude that Rab10 and LRRK2 interact in some, but not all dopaminergic neurons. This may underlie differences in the susceptibility of different human striatal dopaminergic cells to Parkinson’s.

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Contrast Acuity With Different Colors in Parkinson's Disease

Cited by 6 publications

References 27 publications

Multiple Pathways of LRRK2-G2019S/Rab10 Interaction in Dopaminergic Neurons

Multiple Pathways of LRRK2-G2019S/Rab10 Interaction in Dopaminergic Neurons

Retinal Alterations Predict Early Prodromal Signs of Neurodegenerative Disease

Multiple pathways of LRRK2-G2019S / Rab10 interaction in dopaminergic neurons

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