Activation of an actin signaling pathway in pre-malignant mammary epithelial cells by P-cadherin is essential for transformation.

Alterations in the expression or function of cell adhesion molecules have been implicated in all steps of tumor progression. Among those, P-cadherin is highly enriched in basal-like breast carcinomas, playing a central role in cancer cell self-renewal, collective cell migration and invasion. To establish a clinically relevant platform for functional exploration of P-cadherin effectors in vivo, we generated a humanized P-cadherin Drosophila model. We report that actin nucleators, Mrtf and Srf, are main P-cadherin effectors in fly. We validated these findings in a human mammary epithelial cell line with conditional activation of the SRC oncogene. We show that, prior to promoting malignant phenotypes, SRC induces a transient increase in P-cadherin expression, which correlates with MRTF-A accumulation, its nuclear translocation and the upregulation of SRF target genes. Moreover, knocking down P-cadherin, or preventing F-actin polymerization, impairs SRF transcriptional activity. Furthermore, blocking MRTF-A nuclear translocation hampers proliferation, self-renewal and invasion. Thus, in addition to sustaining malignant phenotypes, P-cadherin can also play a major role in the early stages of breast carcinogenesis by promoting a transient boost of MRTF-A-SRF signaling through actin regulation.

Pandemia de COVID-19 no Brasil: quais as repercussões no comportamento, qualidade do sono, uso de telas e alimentação de crianças? / COVID-19 pandemic in Brazil: what are the impactson child behavior, sleep quality, screen time and diet?

Objetivo: Descrever as possíveis repercussões que o distan-ciamento social e pandemia de COVID-19 promoveram no comportamento, qualidade do sono, uso de telas e alimentação de crianças brasileiras de 0 a 12 anos. Materiais e Métodos: Este estudo observacional descritivo foi realizado através de um questionário on-line autoaplicado direcionado aos pais, cuidadores ou responsáveis legais de crianças de 0-12 anos. O questionário foi aplicado entre 19 de agosto de 2020 a 19 de setembro de 2020, em dois grupos, um composto por usuários de serviços de saúde e outro pela população em geral. Os da-dos foram analisados descritivamente, considerando α=5%. Resultados: Compuseram a amostra final 271 respondentes. Segundo os cuidadores, 59,4% das crianças tiveram alterações de comportamento e 48% reportou ou demonstrou medo da COVID-19. Além disso, melhora na qualidade do sono foi reportada de forma importante para crianças de até 2 anos e, 33,3% dos cuidadores em ambos os grupos reportaram piora em qualidade do sono entre 9 e 12 anos. Aumento do uso de telas ocorreu para 85% das crianças. O consumo de alimentos considerados saudáveis se manteve igual para grande parte das crianças e o consumo de alimentos ultraprocessados aumentou para mais de 40% das crianças, principalmente entre 3 e 5 anos e 9 e 12 anos de idade. Discussão: Os resultados encontrados devem ser fonte de atenção a fim de garantir o adequado desenvolvimento infantil após um período de pandemia. Conclusão: O distancia-mento social provocado pela pandemia de COVID-19 promoveu repercussões importantes na rotina das crianças avaliadas, impactando negativamente seu comportamento, alimentação e uso de telas. Ainda, a qualidade do sono de crianças maiores foi impactada negativamente, apesar de ter sido observada melhora na qualidade do sono de crianças mais jovens.

Aim: To describe the potential consequences of social distancing and the COVID-19 pandemic on the behavior, sleep quality, screen time, and diet of Brazilian chil-dren aged 0 to 12 years. Materials and methods: This descriptive observational study was conducted using a self-administered online questionnaire distributed to parents, caregivers or guardians of children aged 0-12 years. The same questionnaire was distributed to two groups between August 19, 2020 and September 19, 2020. Users of Pelotas Public Health Services made up one group, while the general Brazilian population made up the other. The data was analyzed descriptively considering α=5%. Results: The total sample consisted of 271 respondents. According to caregivers, 59.4% of children showed behavioral changes and 48% reported or demonstrated COVID-19 fear. Moreover, improve-ment in sleep quality was reported for children up to 2 years, and 33.3% of caregivers in both groups reported a decline in sleep quality among children aged 9 to 12. Eighty-five percent of children increased their screen time. The intake of healthy foods remained the same for most of the children, but the intake of ultra-processed food increased for over 40% of them, primarily between 3 to 5 years old and 9 to 12 years old. Discussion: The results should be a focus of attention in order to maintain proper child development following a pandemic. Conclusion: The social distancing caused by the COVID-19 pandemic had a significant impact on the children's routine, with negative effects on their behavior, diet and screen time. In addition, a decline in sleep quality was observed among older children, while better sleep quality was reported for younger children.

Heterotypic Amyloid ß interactions facilitate amyloid assembly and modify amyloid structure.

It is still unclear why pathological amyloid deposition initiates in specific brain regions or why some cells or tissues are more susceptible than others. Amyloid deposition is determined by the self-assembly of short protein segments called aggregation-prone regions (APRs) that favour cross-ß structure. Here, we investigated whether Aß amyloid assembly can be modified by heterotypic interactions between Aß APRs and short homologous segments in otherwise unrelated human proteins. Mining existing proteomics data of Aß plaques from AD patients revealed an enrichment in proteins that harbour such homologous sequences to the Aß APRs, suggesting heterotypic amyloid interactions may occur in patients. We identified homologous APRs from such proteins and show that they can modify Aß assembly kinetics, fibril morphology and deposition pattern in vitro. Moreover, we found three of these proteins upon transient expression in an Aß reporter cell line promote Aß amyloid aggregation. Strikingly, we did not find a bias towards heterotypic interactions in plaques from AD mouse models where Aß self-aggregation is observed. Based on these data, we propose that heterotypic APR interactions may play a hitherto unrealized role in amyloid-deposition diseases.

MPV17 Mutations Are Associated With a Quiescent Energetic Metabolic Profile.

Mutations in the MPV17 gene are associated with hepatocerebral form of mitochondrial depletion syndrome. The mechanisms through which MPV17 mutations cause respiratory chain dysfunction and mtDNA depletion is still unclear. The MPV17 gene encodes an inner membrane mitochondrial protein that was recently described to function as a non-selective channel. Although its exact function is unknown, it is thought to be important in the maintenance of mitochondrial membrane potential (ΔΨm). To obtain more information about the role of MPV17 in human disease, we investigated the effect of MPV17 knockdown and of selected known MPV17 mutations associated with MPV17 disease in vitro. We used different approaches in order to evaluate the cellular consequences of MPV17 deficiency. We found that lower levels of MPV17 were associated with impaired mitochondrial respiration and with a quiescent energetic metabolic profile. All the mutations studied destabilized the protein, resulting in reduced protein levels. We also demonstrated that different mutations caused different cellular abnormalities, including increased ROS production, decreased oxygen consumption, loss of ΔΨm, and mislocalization of MPV17 protein. Our study provides novel insight into the molecular effects of MPV17 mutations and opens novel possibilities for testing therapeutic strategies for a devastating group of disorders.

Taxa de ocupação e média de permanência em quatro hospitais de um município sul-brasileiro / Tasa de ocupación y promedio de estancia en cuatro hospitales de un municipio sur-brasileño / Occupancy rate and average stay in four hospitals in a southern Brazilian municipality

Objetivo: avaliar o desempenho dos indicadores taxa de ocupação geral e média de permanência geral em instituições prestadoras do Sistema Único de Saúde em Pelotas, Rio Grande do Sul. Método: estudo quantitativo, descritivo, delineamento dedutivo, em dados secundários do TABWIN, realizado de 2011 a 2015. Resultados: quanto a média de permanência geral, o hospital D esteve dentro do parâmetro. Os demais estavam acima do preconizado, com 9,2 dias de internação. Sobre a taxa de ocupação geral, o hospital A, em 2015, manteve-se no recomendado. O B destacou-se com padrão de 100%. O C, em 2011 e 2012, permaneceu na média, declinando posteriormente. No hospital D, em 2012 e 2013, a média ficou dentro do preconizado, nos demais anos a taxa foi de 89,8%. Conclusões: a média de permanência em um hospital foi dentro do parâmetro. A taxa de ocupação geral em duas entidades foi considerada acima da média.(AU)

Objective: to evaluate the performance indicators general occupancy rate and overall average stay in institutions providing the National Health System in Pelotas, Rio Grande do Sul. Method: quantitative, descriptive study, deductive design, in secondary data from TABWIN, carried out from 2011 to 2015. Results: regarding the overall average stay, hospital D was within the parameter. The other hospitals were above the recommended parameters, with 9.2 days of hospital stay. Regarding the general occupancy rate, hospital A, in 2015, remained as recommended. Hospital B stood out with a 100% pattern. Hospital C remained on average in 2011 and 2012, declining afterwards. In hospital D, the average was within the proposed parameter in 2012 and 2013, in other years the rate was 89.8%. Conclusions: the average hospital stay was within the parameter. The general occupancy rate in two hospital institutions was considered above average.(AU)

Objetivo: evaluar el desarrollo de los indicadores tasa de ocupación general y promedio de estancia general en instituciones del Sistema Único de Salud en Pelotas, Rio Grande del Sur. Método: estudio cuantitativo, descriptivo, en datos secundarios del TABWIN de 2011 a 2015. Resultados: al promedio de estancia, del hospital D, estuvo dentro del parámetro. Los otros estaban a cima del recomendado, con 9,2 días de internación. La tasa de ocupación en el hospital A, en 2015, se mantuvo en el recomendado. El B se destacó, con el 100% estándar. El C, en 2011 y 2012, permaneció en el promedio, declinante posteriormente. En el hospital D, en 2012 y 2013, el promedio quedo dentro del recomendado, en los otros años la tasa fue del 89,8%. Conclusiones: el promedio de estancia en un hospital fue dentro del parámetro. La tasa de ocupación general en dos entidades fue considerada a cima del promedio.(AU)

Reverse engineering synthetic antiviral amyloids.

Human amyloids have been shown to interact with viruses and interfere with viral replication. Based on this observation, we employed a synthetic biology approach in which we engineered virus-specific amyloids against influenza A and Zika proteins. Each amyloid shares a homologous aggregation-prone fragment with a specific viral target protein. For influenza we demonstrate that a designer amyloid against PB2 accumulates in influenza A-infected tissue in vivo. Moreover, this amyloid acts specifically against influenza A and its common PB2 polymorphisms, but not influenza B, which lacks the homologous fragment. Our model amyloid demonstrates that the sequence specificity of amyloid interactions has the capacity to tune amyloid-virus interactions while allowing for the flexibility to maintain activity on evolutionary diverging variants.

Hybrid Epithelial-Mesenchymal Phenotypes Are Controlled by Microenvironmental Factors.

Epithelial-to-mesenchymal transition (EMT) has been associated with cancer cell heterogeneity, plasticity, and metastasis. However, the extrinsic signals supervising these phenotypic transitions remain elusive. To assess how selected microenvironmental signals control cancer-associated phenotypes along the EMT continuum, we defined a logical model of the EMT cellular network that yields qualitative degrees of cell adhesions by adherens junctions and focal adhesions, two features affected during EMT. The model attractors recovered epithelial, mesenchymal, and hybrid phenotypes. Simulations showed that hybrid phenotypes may arise through independent molecular paths involving stringent extrinsic signals. Of particular interest, model predictions and their experimental validations indicated that: (i) stiffening of the extracellular matrix was a prerequisite for cells overactivating FAK_SRC to upregulate SNAIL and acquire a mesenchymal phenotype and (ii) FAK_SRC inhibition of cell-cell contacts through the receptor-type tyrosine-protein phosphatases kappa led to acquisition of a full mesenchymal, rather than a hybrid, phenotype. Altogether, these computational and experimental approaches allow assessment of critical microenvironmental signals controlling hybrid EMT phenotypes and indicate that EMT involves multiple molecular programs. SIGNIFICANCE: A multidisciplinary study sheds light on microenvironmental signals controlling cancer cell plasticity along EMT and suggests that hybrid and mesenchymal phenotypes arise through independent molecular paths.

The spectraplakin Dystonin antagonizes YAP activity and suppresses tumourigenesis.

Aberrant expression of the Spectraplakin Dystonin (DST) has been observed in various cancers, including those of the breast. However, little is known about its role in carcinogenesis. In this report, we demonstrate that Dystonin is a candidate tumour suppressor in breast cancer and provide an underlying molecular mechanism. We show that in MCF10A cells, Dystonin is necessary to restrain cell growth, anchorage-independent growth, self-renewal properties and resistance to doxorubicin. Strikingly, while Dystonin maintains focal adhesion integrity, promotes cell spreading and cell-substratum adhesion, it prevents Zyxin accumulation, stabilizes LATS and restricts YAP activation. Moreover, treating DST-depleted MCF10A cells with the YAP inhibitor Verteporfin prevents their growth. In vivo, the Drosophila Dystonin Short stop also restricts tissue growth by limiting Yorkie activity. As the two Dystonin isoforms BPAG1eA and BPAG1e are necessary to inhibit the acquisition of transformed features and are both downregulated in breast tumour samples and in MCF10A cells with conditional induction of the Src proto-oncogene, they could function as the predominant Dystonin tumour suppressor variants in breast epithelial cells. Thus, their loss could deem as promising prognostic biomarkers for breast cancer.

Correction: The mechanism of sirtuin 2-mediated exacerbation of alpha-synuclein toxicity in models of Parkinson disease.

[This corrects the article DOI: 10.1371/journal.pbio.2000374.].

The APE1 redox inhibitor E3330 reduces collective cell migration of human breast cancer cells and decreases chemoinvasion and colony formation when combined with docetaxel.

The human apurinic/apyrimidinic endonuclease 1 (APE1) is an ubiquitous multifunctional DNA repair enzyme and a redox signalling protein. Our work addressed the inhibition of APE1 redox function using E3330, as single agent or in combination with docetaxel (DTX), in human breast cancer MDA-MB-231 cells. E3330 decreased the colony formation of DTX-treated cells. In addition, E3330 alone significantly reduced the collective cell migration as assessed by the wound-healing assay, whereas the combined treatment decreased chemoinvasion. These results suggest that the inhibition of APE1 redox function might have therapeutic potential by modulating cell migration and invasion in metastatic breast cancer.

The mechanism of sirtuin 2-mediated exacerbation of alpha-synuclein toxicity in models of Parkinson disease.

Sirtuin genes have been associated with aging and are known to affect multiple cellular pathways. Sirtuin 2 was previously shown to modulate proteotoxicity associated with age-associated neurodegenerative disorders such as Alzheimer and Parkinson disease (PD). However, the precise molecular mechanisms involved remain unclear. Here, we provide mechanistic insight into the interplay between sirtuin 2 and α-synuclein, the major component of the pathognomonic protein inclusions in PD and other synucleinopathies. We found that α-synuclein is acetylated on lysines 6 and 10 and that these residues are deacetylated by sirtuin 2. Genetic manipulation of sirtuin 2 levels in vitro and in vivo modulates the levels of α-synuclein acetylation, its aggregation, and autophagy. Strikingly, mutants blocking acetylation exacerbate α-synuclein toxicity in vivo, in the substantia nigra of rats. Our study identifies α-synuclein acetylation as a key regulatory mechanism governing α-synuclein aggregation and toxicity, demonstrating the potential therapeutic value of sirtuin 2 inhibition in synucleinopathies.

Mutant A53T α-Synuclein Improves Rotarod Performance Before Motor Deficits and Affects Metabolic Pathways.

The protein α-synuclein (α-Syn) interferes with glucose and lipid uptake and also activates innate immune cells. However, it remains unclear whether α-Syn or its familial mutant forms contribute to metabolic alterations and inflammation in synucleinopathies, such as Parkinson's disease (PD). Here, we address this issue in transgenic mice for the mutant A53T human α-Syn (α-SynA53T), a mouse model of synucleinopathies. At 9.5 months of age, mice overexpressing α-SynA53T (homozygous) had a significant reduction in weight, exhibited improved locomotion and did not show major motor deficits compared with control transgenic mice (heterozygous). At 17 months of age, α-SynA53T overexpression promoted general reduction in grip strength and deficient hindlimb reflex and resulted in severe disease and mortality in 50 % of the mice. Analysis of serum metabolites further revealed decreased levels of cholesterol, triglycerides and non-esterified fatty acids (NEFA) in α-SynA53T-overexpressing mice. In fed conditions, these mice also showed a significant decrease in serum insulin without alterations in blood glucose. In addition, assessment of inflammatory gene expression in the brain showed a significant increase in TNF-α mRNA but not of IL-1ß induced by α-SynA53T overexpression. Interestingly, the brain mRNA levels of Sirtuin 2 (Sirt2), a deacetylase involved in both metabolic and inflammatory pathways, were significantly reduced. Our findings highlight the relevance of the mechanisms underlying initial weight loss and hyperactivity as early markers of synucleinopathies. Moreover, we found that changes in blood metabolites and decreased brain Sirt2 gene expression are associated with motor deficits.

Structure-based virtual screening toward the discovery of novel inhibitors of the DNA repair activity of the human apurinic/apyrimidinic endonuclease 1.

The DNA repair activity of human apurinic/apyrimidinic endonuclease 1 (APE1) has been recognized as a promising target for the development of small-molecule inhibitors to be used in combination with anticancer agents. In an attempt to identify novel inhibitors of APE1, we present a structure-based virtual screening (SBVS) study based on molecular docking analysis of the compounds of NCI database using the GOLD 5.1.0 (Genetic Optimization for Ligand Docking) suite of programs. Compounds selected in this screening were tested with a fluorescence-based APE1 endonuclease activity assay. Two compounds (37 and 41) were able to inhibit the multifunctional enzyme APE1 in the micromolar range, while compound 22 showed inhibitory effects at nanomolar concentrations. These results were confirmed by a plasmid DNA nicking assay. In addition, the potential APE1 inhibitors did not affect the cell viability of non-tumor MCF10A cells. Overall, compounds 22, 37, and 41 appear to be important scaffolds for the design of novel APE1 inhibitors and this study highlights the relevance of in silico-based approaches as valuable tools in drug discovery.

Ochratoxin A-induced cytotoxicity, genotoxicity and reactive oxygen species in kidney cells: An integrative approach of complementary endpoints.

Ochratoxin A (OTA) is a well-known nephrotoxic and potential carcinogenic agent but no consensus about the molecular mechanisms underlying its deleterious effects has been reached yet. The aim of this study is to integrate several endpoints concerning OTA-induced toxicological effects in Vero kidney cells in order to obtain additional mechanistic data, especially regarding the influence of reactive oxygen species (ROS). One innovative aspect of this work is the use of the superoxide dismutase mimic (SODm) MnTnHex-2-PyP as a mechanistic tool to clarify the involvement of oxidative stress in OTA toxicity. The results showed concentration and time-dependent cytotoxic effects of OTA (crystal violet, neutral red and LDH leakage assays). While the SODm mildly increased cell viability, trolox and ascorbic acid had no effect with regards to this endpoint. OTA induced micronuclei formation. Using the FPG modified comet assay, OTA modestly increased the % of DNA in tail, revealing the presence of oxidative DNA lesions. This mycotoxin increased apoptosis, which was attenuated by SODm. In addition, the SODm decreased the ROS accumulation observed in DHE assay. Taken together, our data suggest that ROS partially contribute to the cytotoxicity and genotoxicity of OTA, although other mechanisms may be relevant in OTA-induced deleterious effects.

LRRK2 Promotes Tau Accumulation, Aggregation and Release.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are known as the most frequent cause of familial Parkinson's disease (PD), but are also present in sporadic cases. The G2019S-LRRK2 mutation is located in the kinase domain of the protein, and has consistently been reported to promote a gain of kinase function. Several proteins have been reported as LRRK2 substrates and/or interactors, suggesting possible pathways involved in neurodegeneration in PD. Hyperphosphorylated Tau protein accumulates in neurofibrillary tangles, a typical pathological hallmark in Alzheimer's disease and frontotemporal dementia. In addition, it is also frequently found in the brains of PD patients. Although LRRK2 is a kinase, it appears that a putative interaction with Tau is phosphorylation-independent. However, the underlying mechanisms and the cellular consequences of this interaction are still unclear. In this study, we demonstrate an interaction between LRRK2 and Tau and that LRRK2 promotes the accumulation of non-monomeric and high-molecular weight (HMW) Tau species independent of its kinase activity. Interestingly, we found that LRRK2 increases Tau secretion, possibly as a consequence of an impairment of Tau proteasomal degradation. Our data highlight a mechanism through which LRRK2 regulates intracellular Tau levels, contributing to the progression of the pathology caused by the LRRK2-mediated proteasome impairment. In total, our findings suggest that the interplay between LRRK2 and proteasome activity might constitute a valid target for therapeutic intervention in PD.

Development of novel sophorolipids with improved cytotoxic activity toward MDA-MB-231 breast cancer cells.

Sophorolipids (SLs) are glycolipid biosurfactants, produced as a mixture of several compounds by some nonpathogenic yeast. In the current study, separation of individual SLs from mixtures with further evaluation of their surface properties and biologic activity on MDA-MB-321 breast cancer cell line were investigated. SLs were biosynthesized by Starmerella bombicola in a culture media supplemented with borage oil. A reverse-phase flash chromatography method with an automated system coupled with a prepacked cartridge was used to separate and purify the main SLs. Compositional analysis of SLs was performed by high-performance liquid chromatography with electrospray ionization mass spectrometry and tandem mass spectrometry. The following diacetylated lactonic SLs were isolated and purified: C18:0, C18:1, C18:2, and C18:3. The critical micelle concentration (CMC) and surface tension at CMC (γCMC ) of the purified SLs showed an increase with the number of double bonds. High cytotoxic effect against MDA-MB-231 cells was observed with C18:0 and C18:1 lactonic SLs. The cytotoxic effects of C18:3 lactonic SL on cancerous cells were for the first time studied. This cytotoxic effect was considerably higher than the promoted by acidic SLs; however, it induced a lower effect than the previously mentioned SLs, C18:0 and C18:1. To our knowledge, for the first time, C18:1 lactonic SL, in selected concentrations, proved to be able to inhibit MDA-MB-231 cell migration without compromising cell viability and to increase intracellular reactive oxygen species.

Systematic comparison of the effects of alpha-synuclein mutations on its oligomerization and aggregation.

Aggregation of alpha-synuclein (ASYN) in Lewy bodies and Lewy neurites is the typical pathological hallmark of Parkinson's disease (PD) and other synucleinopathies. Furthermore, mutations in the gene encoding for ASYN are associated with familial and sporadic forms of PD, suggesting this protein plays a central role in the disease. However, the precise contribution of ASYN to neuronal dysfunction and death is unclear. There is intense debate about the nature of the toxic species of ASYN and little is known about the molecular determinants of oligomerization and aggregation of ASYN in the cell. In order to clarify the effects of different mutations on the propensity of ASYN to oligomerize and aggregate, we assembled a panel of 19 ASYN variants and compared their behaviour. We found that familial mutants linked to PD (A30P, E46K, H50Q, G51D and A53T) exhibited identical propensities to oligomerize in living cells, but had distinct abilities to form inclusions. While the A30P mutant reduced the percentage of cells with inclusions, the E46K mutant had the opposite effect. Interestingly, artificial proline mutants designed to interfere with the helical structure of the N-terminal domain, showed increased propensity to form oligomeric species rather than inclusions. Moreover, lysine substitution mutants increased oligomerization and altered the pattern of aggregation. Altogether, our data shed light into the molecular effects of ASYN mutations in a cellular context, and established a common ground for the study of genetic and pharmacological modulators of the aggregation process, opening new perspectives for therapeutic intervention in PD and other synucleinopathies.

The small GTPase Rab11 co-localizes with α-synuclein in intracellular inclusions and modulates its aggregation, secretion and toxicity.

Alpha-synuclein (aSyn) misfolding and aggregation are pathological features common to several neurodegenerative diseases, including Parkinson's disease (PD). Mounting evidence suggests that aSyn can be secreted and transferred from cell to cell, participating in the propagation and spreading of pathological events. Rab11, a small GTPase, is an important regulator in both endocytic and secretory pathways. Here, we show that Rab11 is involved in regulating aSyn secretion. Rab11 knockdown or overexpression of either Rab11a wild-type (Rab11a WT) or Rab11a GDP-bound mutant (Rab11a S25N) increased secretion of aSyn. Furthermore, we demonstrate that Rab11 interacts with aSyn and is present in intracellular inclusions together with aSyn. Moreover, Rab11 reduces aSyn aggregation and toxicity. Our results suggest that Rab11 is involved in modulating the processes of aSyn secretion and aggregation, both of which are important mechanisms in the progression of aSyn pathology in PD and other synucleinopathies.

α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner.

Alpha-synuclein (αS) misfolding is associated with Parkinson's disease (PD) but little is known about the mechanisms underlying αS toxicity. Increasing evidence suggests that defects in membrane transport play an important role in neuronal dysfunction. Here we demonstrate that the GTPase Rab8a interacts with αS in rodent brain. NMR spectroscopy reveals that the C-terminus of αS binds to the functionally important switch region as well as the C-terminal tail of Rab8a. In line with a direct Rab8a/αS interaction, Rab8a enhanced αS aggregation and reduced αS-induced cellular toxicity. In addition, Rab8 - the Drosophila ortholog of Rab8a - ameliorated αS-oligomer specific locomotor impairment and neuron loss in fruit flies. In support of the pathogenic relevance of the αS-Rab8a interaction, phosphorylation of αS at S129 enhanced binding to Rab8a, increased formation of insoluble αS aggregates and reduced cellular toxicity. Our study provides novel mechanistic insights into the interplay of the GTPase Rab8a and αS cytotoxicity, and underscores the therapeutic potential of targeting this interaction.