Drosophila Model Of Parkinson's Disease Research Articles

Exploring the therapeutic potential of Rab11: A comprehensive study on its effectiveness in alleviating rotenone-induced molecular pathogenesis of Parkinson's disease in SH-SY5Y cells and its synergistic application with L-DOPA in Drosophila models

Dysfunctional mitophagy contributes to Parkinson's disease (PD) by affecting dopamine-producing neurons. Mutations in parkin and pink1 genes, linked to familial PD, impede the removal of damaged mitochondria. Previous studies suggested Rab11's involvement in mitophagy alongside Parkin and Pink1. Additionally, mitochondria-endoplasmic reticulum contact sites (MERCS) regulate cellular functions, including mitochondrial quality control and calcium regulation. Our study explored whether activating mitophagy triggers the unfolded protein response and ER stress pathway in SH-SY5Y human cells. We induced a PD-like state by exposing undifferentiated SH-SY5Y cells to rotenone, an established PD-inducing agent. This led to reduced Rab11 and PERK- expression while increasing ATP5a, a mitochondrial marker, when Rab11 was overexpressed. Our findings suggest that enhancing endosomal trafficking can mitigate ER stress by regulating mitochondria, rescuing cells from apoptosis. Furthermore, we assessed the therapeutic potential of Rab11, both alone and in combination with L-Dopa, in a Drosophila PD model. In summary, our research underscores the role of mitophagy dysfunction in PD pathogenesis, highlighting Rab11's importance in alleviating ER stress and preserving mitochondrial function. It also provides insights into potential PD management strategies, including the synergistic use of Rab11 and L-Dopa.

Polyvinylpyrrolidone-Capped Copper Oxide Nanoparticles-Anchored Pramipexole Attenuates the Rotenone-Induced Phenotypes in a Drosophila Parkinson's Disease Model.

Parkinson's disease (PD) is a progressive, age-related neurodegenerative disease. The disease is characterized by the loss of dopaminergic neurons in the substantia nigra, pars compacta of the midbrain. Pramipexole (PPX) is a novel drug used for the treatment of PD. It has a high affinity for the dopamine (DA) D2 receptor subfamily and acts as a targeted mitochondrial antioxidant. It is less effective in the treatment of PD due to its short half-life, highly inconvenient dosing schedule, and long-term side effects. In recent years, PPX-loaded nanoformulations have been actively reported to overcome these limitations. In the current study, we focused on increasing the effectiveness of PPX by minimizing the dosing frequency and improving the treatment strategy for PD. Herein, we report the synthesis of biodegradable polyvinylpyrrolidone (PVP)-capped copper oxide nanoparticles (PVP-CuO NPs), followed by PPX anchoring on the surface of the PVP-CuO NPs (PPX-PVP-CuO NC), in a simple and inexpensive method. The newly formulated PPX-PVP-CuO NC complex was analyzed for its chemical and physical properties. The PPX-PVP-CuO NC was tested to protect against rotenone (RT)-induced toxicity in the Drosophila PD model. The in vivo studies using the RT-induced Drosophila PD model showed significant changes in negative geotaxis behavior and the level of DA and acetylcholinesterase. In addition, oxidative stress markers such as glutathione-S-transferase, total glutathione, thiobarbituric acid reactive species, and protein carbonyl content showed significant amelioration. The positive changes of PPX-PVP-CuO NC treatment in behavior, neurotransmitter level, and antioxidant level suggest its potential role in mitigating the PD phenotype. The formulation can be used for treatment or pharmacological intervention against PD.

Quassinoids from Twigs of Harrisonia perforata (Blanco) Merr and Their Anti-Parkinson's Disease Effect.

Six new C-20 and one new C-19 quassinoids, named perforalactones F-L (1-7), were isolated from twigs of Harrisonia perforata. Spectroscopic and X-ray crystallographic experiments were conducted to identify their structures. Through oxidative degradation of perforalactone B to perforaqussin A, the biogenetic process from C-25 quassinoid to C-20 via Baeyer-Villiger oxidation was proposed. Furthermore, the study evaluated the anti-Parkinson's disease potential of these C-20 quassinoids for the first time on 6-OHDA-induced PC12 cells and a Drosophila Parkinson's disease model of PINK1B9. Perforalactones G and I (2 and 4) showed a 10-15% increase in cell viability of the model cells at 50 μM, while compounds 2 and 4 (100 μM) significantly improved the climbing ability of PINK1B9 flies and increased the dopamine level in the brains and ATP content in the thoraces of the flies.

Kanamycin treatment in the pre-symptomatic stage of a Drosophila PD model prevents the onset of non-motor alterations

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor alterations, which is preceded by a prodromal stage where non-motor symptoms are observed. Over recent years, it has become evident that this disorder involves other organs that communicate with the brain like the gut. Importantly, the microbial community that lives in the gut plays a key role in this communication, the so-called microbiota-gut-brain axis. Alterations in this axis have been associated to several disorders including PD.Here we proposed that the gut microbiota is different in the presymptomatic stage of a Drosophila model for PD, the Pink1B9 mutant fly, as compared to that observed in control animals. Our results show this is the case: there is basal dysbiosis in mutant animals evidenced by substantial difference in the composition of midgut microbiota in 8–9 days old Pink1B9 mutant flies as compared with control animals. Further, we fed young adult control and mutant flies kanamycin and analyzed motor and non-motor behavioral parameters in these animals. Data show that kanamycin treatment induces the recovery of some of the non-motor parameters altered in the pre-motor stage of the PD fly model, while there is no substantial change in locomotor parameters recorded at this stage. On the other hand, our results show that feeding young animals the antibiotic, results in a long-lasting improvement of locomotion in control flies.Our data support that manipulations of gut microbiota in young animals could have beneficial effects on PD progression and age-dependent motor impairments.This article is part of the Special Issue on “Microbiome & the Brain: Mechanisms & Maladies”.

Impact of age on the rotenone-induced sporadic Parkinson's disease model using Drosophila melanogaster

Rotenone, a naturally occurring toxin, has been used to induce sporadic Parkinson's disease (PD) in Drosophila melanogaster for decades. However, the age of flies varies considerably between studies in this model. To investigate the impact of age on the rotenone-induced PD model, we collected male flies at the age of 1, 5, 7, and 10 days post-eclosion, respectively. Then, flies were immediately exposed to a feeding medium supplemented with 250 μM rotenone for seven days. The motor ability of Drosophila was detected by negative geotaxis assay, and the number of dopamine (DA) neurons and tyrosine hydroxylase (TH) expression levels were evaluated. The results showed that both the motor deficits and mortality increased with age. The flies older than five days showed typical PD features, including the loss of DA neurons, decreased TH expression levels, and decreased locomotive ability. However, 1-day-old flies displayed an unstable motor deficit and little TH expression changes after seven days of rotenone exposure. Lastly, after 7 days of exposure to rotenone, the death rate of flies rapidly increased with increasing starting age. The death rates of 1-, 5-, 7-, and 10-days old flies were 10.0%, 22.8%, 41.5%, and 50.4%, respectively. The findings of this study suggest that age is a crucial factor impacting the Drosophila PD model. This information provides a reference for the age selection to use this model for future studies.

Melatonin Mitigates Rotenone-Induced Oxidative Stress and Mitochondrial Dysfunction in the Drosophila melanogaster Model of Parkinson's Disease-like Symptoms.

Parkinson's disease (PD) is the second most common neurodegenerative disorder; however, its etiology remains elusive. Antioxidants are considered to be a promising approach for decelerating neurodegenerative disease progression owing to extensive examination of the relationship between oxidative stress and neurodegenerative diseases. In this study, we investigated the therapeutic effect of melatonin against rotenone-induced toxicity in the Drosophila model of PD. The 3-5 day old flies were divided into four groups: control, melatonin alone, melatonin and rotenone, and rotenone alone groups. According to their respective groups, flies were exposed to a diet containing rotenone and melatonin for 7 days. We found that melatonin significantly reduced the mortality and climbing ability of Drosophila because of its antioxidative potency. It alleviated the expression of Bcl 2, tyrosine hydroxylase (TH), NADH dehydrogenase, mitochondrial membrane potential, and mitochondrial bioenergetics and decreased caspase 3 expression in the Drosophila model of rotenone-induced PD-like symptoms. These results indicate the neuromodulatory effect of melatonin, and that it is likely modulated against rotenone-induced neurotoxicity by suppressing oxidative stress and mitochondrial dysfunctions.

Nicotine-Mediated Rescue of α-Synuclein Toxicity Requires Synaptic Vesicle Glycoprotein 2 in Drosophila.

Parkinson's disease (PD) is characterized by α-synuclein aggregation and loss of dopamine neurons. Risk of PD arises due to a combination of genetic and environmental factors, which may interact, termed gene-environment (G×E) interactions. An inverse association between smoking and the risk of PD is well established, and a previous genome-wide G×E interaction study identified genetic variation in the synaptic-vesicle glycoprotein 2C (SV2C) locus as an important mediator of the degree to which smoking is inversely associated with PD. We sought to determine the mechanism of the smoking-SV2C interaction in a Drosophila model of PD. Flies expressing human α-synuclein in all neurons develop the hallmarks of PD, including motor dysfunction, loss of dopaminergic (DA) neurons, and formation of α-synuclein inclusions. We assessed the effects of increasing doses of nicotine on these parameters of neurodegeneration, in the presence or absence of knockdown of two Drosophila orthologues of SV2, hereafter referred to as SV2L1 and SV2L2. The α-synuclein-expressing flies treated with nicotine had improved locomotion, DA neuron counts, and α-synuclein aggregation. However, in α-synuclein-expressing flies in which SV2L1 and SV2L2 were knocked down, nicotine failed to rescue neurodegeneration. This work confirms a G×E interaction between nicotine and SV2, defines a role for this interaction in α-synuclein proteostasis, and suggests that future clinical trials on nicotine should consider genetic variation in SV2C. Furthermore, this provides proof of concept that our model can be used for the mechanistic study of G×E, paving the way for the investigation of additional G×E interactions or the identification of novel G×E. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Neuroprotective Effects of Lycium Barbarum Fruit Extract on Pink1B9Drosophila Melanogaster Genetic Model of Parkinson's Disease.

Lycium barbarum (LB) is a famous traditional Chinese medicinal plant as well as food supplement possessing various pharmacological functions such as anti-aging and antioxidant effects. The Parkinson's disease (PD)-related kinase Pink1 plays vital role in maintaining the neuron cell homeostasis, having been recognized as a potential target for the development of anti-PD drugs. In this work, the neuroprotective effects of methanol extract of LB fruit (LBFE) were investigated using a Drosophila PD model (PINK1B9) and a human neuroblastoma SH-SY5Y cell line. We found that when LBFE was supplied to the PINK1B9 flies at 6, 12, and 18 days of age, it raised the ATP and dopamine levels at all ages, extended life span, improved motor behavior, and rescued olfactory deficits of the PINK1B9 flies. In addition, histopathological examinations indicated that muscle atrophy in thoraces of the mutant flies was significantly repaired. Finally, LBFE was able to rescue the SH-SY5Y cells against MPP+-induced neurotoxicity. This work reports for the first time the anti-PD potential of L. barbarum fruit extract in PINK1 mutant fruit flies, presenting a new viewpoint for studing the mechanism of action of LBFE.

Lamp1 Deficiency Enhances Sensitivity to α-Synuclein and Oxidative Stress in Drosophila Models of Parkinson Disease.

Parkinson disease (PD) is a common neurodegenerative condition affecting people predominantly at old age that is characterized by a progressive loss of midbrain dopaminergic neurons and by the accumulation of α-synuclein-containing intraneuronal inclusions known as Lewy bodies. Defects in cellular degradation processes such as the autophagy-lysosomal pathway are suspected to be involved in PD progression. The mammalian Lysosomal-associated membrane proteins LAMP1 and LAMP2 are transmembrane glycoproteins localized in lysosomes and late endosomes that are involved in autophagosome/lysosome maturation and function. Here, we show that the lack of Drosophila Lamp1, the homolog of LAMP1 and LAMP2, severely increased fly susceptibility to paraquat, a pro-oxidant compound known as a potential PD inducer in humans. Moreover, the loss of Lamp1 also exacerbated the progressive locomotor defects induced by the expression of PD-associated mutant α-synuclein A30P (α-synA30P) in dopaminergic neurons. Remarkably, the ubiquitous re-expression of Lamp1 in a mutant context fully suppressed all these defects and conferred significant resistance towards both PD factors above that of wild-type flies. Immunostaining analysis showed that the brain levels of α-synA30P were unexpectedly decreased in young adult Lamp1-deficient flies expressing this protein in comparison to non-mutant controls. This suggests that Lamp1 could neutralize α-synuclein toxicity by promoting the formation of non-pathogenic aggregates in neurons. Overall, our findings reveal a novel role for Drosophila Lamp1 in protecting against oxidative stress and α-synuclein neurotoxicity in PD models, thus furthering our understanding of the function of its mammalian homologs.

Integration of transcriptome-wide association study with neuronal dysfunction assays provides functional genomics evidence for Parkinson's disease genes.

Genome-wide association studies (GWAS) have markedly advanced our understanding of the genetics of Parkinson's disease (PD), but they currently do not account for the full heritability of PD. In many cases it is difficult to unambiguously identify a specific gene within each locus because GWAS does not provide functional information on the identified candidate loci. Here we present an integrative approach that combines transcriptome-wide association study (TWAS) with high-throughput neuronal dysfunction analyses in Drosophila to discover and validate candidate PD genes. We identified 160 candidate genes whose misexpression is associated with PD risk via TWAS. Candidates were validated using orthogonal in silico methods and found to be functionally related to PD-associated pathways (i.e. endolysosome). We then mimicked these TWAS-predicted transcriptomic alterations in a Drosophila PD model and discovered that 50 candidates can modulate α-Synuclein(α-Syn)-induced neurodegeneration, allowing us to nominate new genes in previously known PD loci. We also uncovered additional novel PD candidate genes within GWAS suggestive loci (e.g. TTC19, ADORA2B, LZTS3, NRBP1, HN1L), which are also supported by clinical and functional evidence. These findings deepen our understanding of PD, and support applying our integrative approach to other complex trait disorders.

Exploring the link between Parkinson's disease and type 2 diabetes mellitus in Drosophila.

Parkinson's disease (PD) is the second most common neurodegenerative disease. Diabetes mellitus (DM) is a metabolic disease characterized by high levels of glucose in blood. Recent epidemiological studies have highlighted the link between both diseases; it is even considered that DM might be a risk factor for PD. To further investigate the likely relation of these diseases, we have used a Drosophila PD model based on inactivation of the DJ-1β gene (ortholog of human DJ-1), and diet-induced Drosophila and mouse type 2 DM (T2DM) models, together with human neuron-like cells. T2DM models were obtained by feeding flies with a high sugar-containing medium, and mice with a high fat diet. Our results showed that both fly models exhibit common phenotypes such as alterations in carbohydrate homeostasis, mitochondrial dysfunction or motor defects, among others. In addition, we demonstrated that T2DM might be a risk factor of developing PD since our diet-induced fly and mouse T2DM models present DA neuron dysfunction, a hallmark of PD. We also confirmed that neurodegeneration is caused by increased glucose levels, which has detrimental effects in human neuron-like cells by triggering apoptosis and leading to cell death. Besides, the observed phenotypes were exacerbated in DJ-1β mutants cultured in the high sugar medium, indicating that DJ-1 might have a role in carbohydrate homeostasis. Finally, we have confirmed that metformin, an antidiabetic drug, is a potential candidate for PD treatment and that it could prevent PD onset in T2DM model flies. This result supports antidiabetic compounds as promising PD therapeutics.

Analysis of Dopaminergic Functions in Drosophila.

Dopaminergic (DA) neurons regulate various physiological functions, including motor function, emotion, learning, sleep, and arousal. Degeneration of DA neurons in the substantia nigra of the midbrain causes motor disturbance in Parkinson's disease (PD). Studies on familial PD have revealed that a subset of PD genes encode proteins that regulate mitochondrial function and synaptic dynamics. Drosophila is a powerful model of PD, whereby genetic interactions of PD genes with well-conserved cellular signaling can be evaluated. Morphological changes in mitochondria, along with dysfunction and degeneration of DA neurons, have been reported in many studies using Drosophila PD models. In this chapter, we will describe imaging methods to visualize mitochondria in DA neurons and to evaluate spontaneous neural activity of DA neurons in the Drosophila brain.

Attenuation of epigenetic regulator SMARCA4 and ERK-ETS signaling suppresses aging-related dopaminergic degeneration.

How complex interactions of genetic, environmental factors and aging jointly contribute to dopaminergic degeneration in Parkinson's disease (PD) is largely unclear. Here, we applied frequent gene co‐expression analysis on human patient substantia nigra‐specific microarray datasets to identify potential novel disease‐related genes. In vivo Drosophila studies validated two of 32 candidate genes, a chromatin‐remodeling factor SMARCA4 and a biliverdin reductase BLVRA. Inhibition of SMARCA4 was able to prevent aging‐dependent dopaminergic degeneration not only caused by overexpression of BLVRA but also in four most common Drosophila PD models. Furthermore, down‐regulation of SMARCA4 specifically in the dopaminergic neurons prevented shortening of life span caused by α‐synuclein and LRRK2. Mechanistically, aberrant SMARCA4 and BLVRA converged on elevated ERK‐ETS activity, attenuation of which by either genetic or pharmacological manipulation effectively suppressed dopaminergic degeneration in Drosophila in vivo. Down‐regulation of SMARCA4 or drug inhibition of MEK/ERK also mitigated mitochondrial defects in PINK1 (a PD‐associated gene)‐deficient human cells. Our findings underscore the important role of epigenetic regulators and implicate a common signaling axis for therapeutic intervention in normal aging and a broad range of age‐related disorders including PD.

Ropinirole silver nanocomposite attenuates neurodegeneration in the transgenic Drosophila melanogaster model of Parkinson's disease

Parkinson's disease (PD) is a progressive neurodegenerative disease due to the degeneration of dopaminergic neurons in substantia nigra pars compacta of the mid brain. The present study investigates the neuro-protective role of synthesized ropinirole silver nanocomposite (RPAgNC) in Drosophila model of PD. α-synuclein accumulation in the brain of flies (PD flies) leads to the damage of dopaminergic neurons, dopamine depletion, impaired muscular coordination, memory decline and increase in oxidative stress. Ingestion of the RPAgNC by Drosophila significantly prevented the neuronal degeneration compared to only ropinirole. The results confirm that the RPAgNC exerts more neuro-protective effect compared to dopamine agonist i.e. ropinirole as such drug in experimental PD flies.This article is part of the special issue entitled ‘The Quest for Disease-Modifying Therapies for Neurodegenerative Disorders’.

Drosophila Skp1 Homologue SkpA Plays a Neuroprotective Role in Adult Brain

SummarySkp1, a component of the ubiquitin E3 ligases, was found to be decreased in the brains of sporadic Parkinson's disease (PD) patients, and its overexpression prevented death of murine neurons in culture. Here we expose the neuroprotective role of the Drosophila skp1 homolog, skpA, in the adult brain. Neuronal knockdown of skpA leads to accumulation of ubiquitinated protein aggregates and loss of dopaminergic neurons accompanied by motor dysfunction and reduced lifespan. Conversely, neuronal overexpression of skpA reduces aggregate load, improves age-related motor decline, and prolongs lifespan. Moreover, SkpA rescues neurodegeneration in a Drosophila model of PD. We also show that a Drosophila homolog of FBXO7, the F Box protein, Nutcracker (Ntc), works in the same pathway with SkpA. However, skpA overexpression rescues ntc knockdown phenotype, suggesting that SkpA interacts with additional F box proteins in the adult brain neurons. Collectively, our study discloses Skp1/SkpA as a potential therapeutic target in neurodegenerative diseases.

Polydatin protects SH-SY5Y in models of Parkinson's disease by promoting Atg5-mediated but parkin-independent autophagy

Parkinson's disease (PD), the second most common chronic neurodegenerative disorder, broadly remains incurable. Both genetic susceptibility and exposure to deleterious environmental stimuli contribute to dopaminergic neuron degeneration in the substantia nigra. Hence, reagents that can ameliorate the phenotypes rendered by genetic or environmental factors should be considered in PD therapy. In this study, we found that polydatin (Pol), a natural compound extracted from grapes and red wines, significantly attenuated rotenone- (Rot) or Parkin deficiency-induced mitochondrial dysfunction and cell death in SH-SY5Y, a human dopaminergic neuronal cell line. We showed that Pol significantly attenuated the Rot-induced decrease in cell viability, mitochondrial membrane potential (MMP), and Sirt 1 expression and increase in cell death, reactive oxygen species (ROS) and DJ1 expression. Rot resulted in a decrease in mTOR/Ulk-involved autophagy and an increase in PGC1β/mfn2-involved mitochondrial fusion, which was inhibited by Pol. We further demonstrated that the protective effects of Pol are partially blocked when autophagy-related gene 5 (Atg5) is genetically inactivated, suggesting that Pol-mediated neuroprotection requires Atg5. Moreover, Pol rescued Parkin knockdown-induced oxidative stress, mitochondrial dysfunction, autophagy impairment, and mitochondrial fusion enhancement. Interestingly, Pol treatment could also rescue the mitochondrial morphological abnormality and motorial dysfunction of a Drosophila PD model induced by Parkin deficiency. Thus, Pol could represent a useful therapeutic strategy as a disease-modifier in PD by decreasing oxidative stress and regulating autophagic processes and mitochondrial fusion.

Targeting UCH in Drosophila melanogaster as a model for Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disease caused by genetic or environmental factors. Among several animal models, the Drosophila melanogaster is one of the valuable models widely used in studying genes and proteins implicated in PD. UCH-L1 (Ubiquitin carboxyl-terminal hydrolase L1) which is involved in formation of Lewy bodies, shows loss of function mutations in PD causing degeneration of dopaminergic neurons in mice. Here, we summarize the results from studying the UCH-L1 and its knockdown in Drosophila model of PD with respect to movement, degeneration of dopamine producing neurons, dopamine deficiency and age dependent dependency of progression of the disease. The knockdown of the UCH-L1 in Drosophila can be used in studying the epidemiology of the disease as well as in drug screening for finding therapeutic targets for PD.

Neuroprotective function of Omi to α-synuclein-induced neurotoxicity

The main pathological hallmark of Parkinson's disease (PD) is the presence of Lewy bodies, which mainly consist of aggregated α-synuclein. Based on the neurotoxicity of oligomeric α-synuclein and its significance in the aetiology of PD, there has been decades of effort to elucidate an enzyme specifically degrading oligomeric α-synuclein. Here we report an enzyme, Omi, which specifically recognizes and precisely degrades oligomeric α-synuclein but not monomeric α-synuclein. After enzymatic and functional analyses of Omi in in vitro, we developed an in vivo assay system of dual gene interaction in Drosophila to investigate further the etiological role of Omi in PD. Pan-neuronal expression of Omi rescued Parkinsonism in a Drosophila model of PD, while Knockout of Omi exacerbated Parkinsonism. Expression of Omi counteracted the α-synuclein-induced retinal degeneration, providing additional evidence for Omi's protective role oligomeric α-synuclein. This work reports identification of the catabolic pathway of oligomeric α-synuclein as well as showing how Omi functions as the key molecule in the recognition and degradation of toxic oligomeric α-synuclein, a possible cause of neurodegeneration in PD, without affecting monomeric α-synuclein which is a native essential molecule for the normal function of neurons.

A locomotor assay reveals deficits in heterozygous Parkinson’s disease model and proprioceptive mutants in adult Drosophila

Severe locomotor impairment is a common phenotype of neurodegenerative disorders such as Parkinson's disease (PD). Drosophila models of PD, studied for more than a decade, have helped in understanding the interaction between various genetic factors, such as parkin and PINK1, in this disease. To characterize locomotor behavioral phenotypes for these genes, fly climbing assays have been widely used. While these simple current assays for locomotor defects in Drosophila mutants measure some locomotor phenotypes well, it is possible that detection of subtle changes in behavior is important to understand the manifestation of locomotor disorders. We introduce a climbing behavior assay which provides such fine-scale behavioral data and tests this proposition for the Drosophila model. We use this inexpensive, fully automated assay to quantitatively characterize the climbing behavior at high parametric resolution in 3 contexts. First, we characterize wild-type flies and uncover a hitherto unknown sexual dimorphism in climbing behavior. Second, we study climbing behavior of heterozygous mutants of genes implicated in the fly PD model and reveal previously unreported prominent locomotor defects in some of these heterozygous fly lines. Finally, we study locomotor defects in a homozygous proprioceptory mutation (Trp-γ1 ) known to affect fine motor control in Drosophila Moreover, we identify aberrant geotactic behavior in Trp-γ1 mutants, thereby opening up a finer assay for geotaxis and its genetic basis. Our assay is therefore a cost-effective, general tool for measuring locomotor behaviors of wild-type and mutant flies in fine detail and can reveal subtle motor defects.

α-Arbutin Protects Against Parkinson's Disease-Associated Mitochondrial Dysfunction In Vitro and In Vivo.

Parkinson's disease (PD), the most common neurodegenerative movement disorder, is characterized by the progressive loss of dopaminergic neurons in substantia nigra. The underlying mechanisms of PD pathogenesis have not been fully illustrated and currently PD remains incurable. Accumulating evidences suggest that mitochondrial dysfunction plays pivotal role in the dopaminergic neuronal death. Therefore, discovery of novel and safe agent for rescuing mitochondrial dysfunction would benefit PD treatment. Here we demonstrated for the first time that α-Arbutin (Arb), a natural polyphenol extracted from Ericaceae species, displayed significant protective effect on the rotenone (Rot)-induced mitochondrial dysfunction and apoptosis of human neuroblastoma cell (SH-SY5Y). We further found that the neuroprotective effect of Arb was associated with ameliorating oxidative stress, stabilizing of mitochondrial membrane potential, and enhancing adenosine triphosphate production. To investigate the underlying mechanism, we checked the AMP-activated protein kinase and autophagy pathway and we found that both were involved in the neuroprotection of Arb. Moreover, we explored the protective effect of Arb in drosophila PD model and found that Arb rescued parkin deficiency-induced motor function disability and mitochondrial abnormality of drosophila. Taken together, our study demonstrated that Arb got excellent neuroprotective effect on PD models both in vitro and in vivo and Arb might serve as a potent therapeutic agent for the treatment of PD.