Abnormal visual gain control and excitotoxicity in early-onset Parkinson’s disease Drosophila models

Abstract

The excitotoxic theory of Parkinson’s disease (PD) hypothesizes that a pathophysiological degeneration of dopaminergic neurons stems from neural hyperactivity at early stages of disease, leading to mitochondrial stress and cell death. Recent research has harnessed the visual system of Drosophila PD models to probe this hypothesis. Here, we investigate whether abnormal visual sensitivity and excitotoxicity occur in early-onset PD (EOPD) Drosophila models DJ-1αΔ72, DJ-1βΔ93, and PINK15. We used an electroretinogram to record steady-state visually evoked potentials driven by temporal contrast stimuli. At 1 day of age, all EOPD mutants had a twofold increase in response amplitudes compared with w̄ controls. Furthermore, we found that excitotoxicity occurs in older EOPD models after increased neural activity is triggered by visual stimulation. In an additional analysis, we used a linear discriminant analysis to test whether there were subtle variations in neural gain control that could be used to classify Drosophila into their correct age and genotype. The discriminant analysis was highly accurate, classifying Drosophila into their correct genotypic class at all age groups at 50–70% accuracy (20% chance baseline). Differences in cellular processes link to subtle alterations in neural network operation in young flies, all of which lead to the same pathogenic outcome. Our data are the first to quantify abnormal gain control and excitotoxicity in EOPD Drosophila mutants. We conclude that EOPD mutations may be linked to more sensitive neuronal signaling in prodromal animals that may cause the expression of PD symptomologies later in life.NEW & NOTEWORTHY Steady-state visually evoked potential response amplitudes to multivariate temporal contrast stimuli were recorded in early-onset PD Drosophila models. Our data indicate that abnormal gain control and a subsequent visual loss occur in these PD mutants, supporting a broader excitotoxicity hypothesis in genetic PD. Furthermore, linear discriminant analysis could accurately classify Drosophila into their correct genotype at different ages throughout their lifespan. Our results suggest increased neural signaling in prodromal PD patients.

Dopamine, Alpha-Synuclein, and Mitochondrial Dysfunctions in Parkinsonian Eyes

“…This hypothesis is supported by experimental evidence showing that α-Syn fibrils can spread across brain regions and more recent findings show that they can move from the gut to the brain (Challis et al, 2020). According to this hypothesis the eyes should be one of the first organs affected if fibrils spread from the nose, as previously suggested (Choudhry and Perlmuter, 2017), which would be in line with clinical and pre-clinical findings reporting specific visual symptoms in early stages of PD or dementia with Lewy bodies (DLB) (Armstrong, 2015;Himmelberg et al, 2018;Chung et al, 2019).…”

“…More recently, a comparison of visual function among Drosophila models carrying the early-onset PD mutations DJ-1α 72 , DJ-1β 93 , and PINK1 5 (Himmelberg et al, 2018) has been performed. In order to investigate the consequences of the above mutations on the response of neuronal populations in the retina, the authors recorded steady-state VEP (SSVEP) from the surface of the Drosophila eye following stimulation with a sequence of frequencytagged flickering stimuli.…”

In vivovisual screen for dopaminergicRab ↔ LRRK2-G2019Sinteractions inDrosophiladiscriminatesRab10fromRab3

“…The visual response of 108 flies stimulated with a flickering blue light was recorded. Young, 4-12 hour 109 old, PD-mimic flies show visual hyperexcitability, particularly in the lamina 110 neurons (Afsari et al 2014;Himmelberg et al 2017). This includes the THG2 111 flies.…”

In Vivo Visual Screen for Dopaminergic Rab ↔ LRRK2-G2019S Interactions in Drosophila Discriminates Rab10 from Rab3

“…The visual response of flies stimulated with a flickering blue light was recorded. Young, 4-12 hour old, PD-mimic flies show visual hyperexcitability, particularly in the lamina neurons (Afsari et al 2014;Himmelberg et al 2017). This includes the THG2 flies.…”