Kidins220 deficiency causes ventriculomegaly via SNX27-retromer-dependent AQP4 degradation

Several psychiatric, neurologic and neurodegenerative disorders present increased brain ventricles volume, being hydrocephalus the disease with the major manifestation of ventriculomegaly caused by the accumulation of high amounts of cerebrospinal fluid (CSF). The molecules and pathomechanisms underlying cerebral ventricular enlargement are widely unknown. Kinase D interacting substrate of 220 kDa (KIDINS220) gene has been recently associated with schizophrenia and with a novel syndrome characterized by spastic paraplegia, intellectual disability, nystagmus and obesity (SINO syndrome), diseases frequently occurring with ventriculomegaly. Here we show that Kidins220, a transmembrane protein effector of various key neuronal signalling pathways, is a critical regulator of CSF homeostasis. We observe that both KIDINS220 and the water channel aquaporin-4 (AQP4) are markedly downregulated at the ventricular ependymal lining of idiopathic normal pressure hydrocephalus (iNPH) patients. We also find that Kidins220 deficient mice develop ventriculomegaly accompanied by water dyshomeostasis and loss of AQP4 in the brain ventricular ependymal layer and astrocytes. Kidins220 is a known cargo of the SNX27-retromer, a complex that redirects endocytosed plasma membrane proteins (cargos) back to the cell surface, thus avoiding their targeting to lysosomes for degradation. Mechanistically, we show that AQP4 is a novel cargo of the SNX27-retromer and that Kidins220 deficiency promotes a striking and unexpected downregulation of the SNX27-retromer that results in AQP4 lysosomal degradation. Accordingly, SNX27 silencing decreases AQP4 levels in wild-type astrocytes whereas SNX27 overexpression restores AQP4 content in Kidins220 deficient astrocytes. Together our data suggest that the KIDINS220-SNX27-retromer-AQP4 pathway is involved in human ventriculomegaly and open novel therapeutic perspectives

Is inhibition of kinase activity the only therapeutic strategy for LRRK2-associated Parkinson's disease?

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are a common cause of familial Parkinson's disease (PD). Variation around the LRRK2 locus also contributes to the risk of sporadic PD. The LRRK2 protein contains a central catalytic region, and pathogenic mutations cluster in the Ras of complex protein C terminus of Ras of complex protein (mutations N1437H, R1441G/C and Y1699C) and kinase (G2019S and I2020T) domains. Much attention has been focused on the kinase domain, because kinase-dead versions of mutant LRRK2 are less toxic than kinase-active versions of the same proteins. Furthermore, kinase inhibitors may be able to mimic this effect in mouse models, although the currently tested inhibitors are not completely specific. In this review, we discuss the recent progress in the development of specific LRRK2 kinase inhibitors. We also discuss non-kinase-based therapeutic strategies for LRRK2-associated PD as it is possible that different approaches may be needed for different mutations

Human oocyte-derived methylation differences persist in the placenta revealing widespread transient imprinting

Thousands of regions in gametes have opposing methylation profiles that are largely resolved during the post-fertilization epigenetic reprogramming. However some specific sequences associated with imprinted loci survive this demethylation process. Here we present the data describing the fate of germline-derived methylation in humans. With the exception of a few known paternally methylated germline differentially methylated regions (DMRs) associated with known imprinted domains, we demonstrate that sperm-derived methylation is reprogrammed by the blastocyst stage of development. In contrast a large number of oocyte-derived methylation differences survive to the blastocyst stage and uniquely persist as transiently methylated DMRs only in the placenta. Furthermore, we demonstrate that this phenomenon is exclusive to primates, since no placenta-specific maternal methylation was observed in mouse. Utilizing single cell RNA-seq datasets from human preimplantation embryos we show that following embryonic genome activation the maternally methylated transient DMRs can orchestrate imprinted expression. However despite showing widespread imprinted expression of genes in placenta, allele-specific transcriptional profiling revealed that not all placenta-specific DMRs coordinate imprinted expression and that this maternal methylation may be absent in a minority of samples, suggestive of polymorphic imprinted methylation

A modern guide to quantitative spectroscopy of massive OB stars

Quantitative spectroscopy is a powerful technique from which we can extract information about the physical properties and surface chemical composition of stars. In this chapter, I guide the reader through the main ideas required to get initiated in the learning process to become an expert in the application of state-of-the-art quantitative spectroscopic techniques to the study of massive OB stars. NB: This chapter is intended to serve to young students as a first approach to a field which has attracted my attention during the last 20 years. I should note that, despite its importance, at present, the number of real experts in the field around the world is limited to less than 50 people, and about one third of them are close to retirement. Hence, I consider that this is a good moment to write a summary text on the subject to serve as guideline for the next generations of students interested in joining the massive star crew. If you are one of them, please, use this chapter as a first working notebook. Do not stop here. Dig also, for further details, into the literature I quote along the text. And, once there, dig even deeper to find all the original sources explaining in more detail the physical and technical concepts that are presently incorporated into our modern (almost) automatized tools.Comment: Accepted for publication in the book "Reviews in Frontiers of Modern Astrophysics: From Space Debris to Cosmology" (eds Kabath, Jones and Skarka; publisher Springer Nature) funded by the European Union Erasmus+ Strategic Partnership grant "Per Aspera Ad Astra Simul" 2017-1-CZ01-KA203-03556

Electroluminescence TPCs at the thermal diffusion limit

[EN] The NEXT experiment aims at searching for the hypothetical neutrinoless double-beta decay from the 136Xe isotope using a high-purity xenon TPC. Efficient discrimination of the events through pattern recognition of the topology of primary ionisation tracks is a major requirement for the experiment. However, it is limited by the diffusion of electrons. It is known that the addition of a small fraction of a molecular gas to xenon reduces electron diffusion. On the other hand, the electroluminescence (EL) yield drops and the achievable energy resolution may be compromised. We have studied the effect of adding several molecular gases to xenon (CO2, CH4 and CF4) on the EL yield and energy resolution obtained in a small prototype of driftless gas proportional scintillation counter. We have compared our results on the scintillation characteristics (EL yield and energy resolution) with a microscopic simulation, obtaining the diffusion coefficients in those conditions as well. Accordingly, electron diffusion may be reduced from about 10 mm/ sqrt(¿) for pure xenon down to 2.5 mm/sqrt(m) using additive concentrations of about 0.05%, 0.2% and 0.02% for CO2, CH4 and CF4, respectively. Our results show that CF4 admixtures present the highest EL yield in those conditions, but very poor energy resolution as a result of huge fluctuations observed in the EL formation. CH4 presents the best energy resolution despite the EL yield being the lowest. The results obtained with xenon admixtures are extrapolated to the operational conditions of the NEXT-100 TPC. CO2 and CH4 show potential as molecular additives in a large xenon TPC. While CO2 has some operational constraints, making it difficult to be used in a large TPC, CH4 shows the best performance and stability as molecular additive to be used in the NEXT-100 TPC, with an extrapolated energy resolution of 0.4% at 2.45 MeV for concentrations below 0.4%, which is only slightly worse than the one obtained for pure xenon. We demonstrate the possibility to have an electroluminescence TPC operating very close to the thermal diffusion limit without jeopardizing the TPC performance, if CO2 or CH4 are chosen as additives.The NEXT Collaboration acknowledges support from the following agencies and institutions: the European Research Council (ERC) under the Advanced Grant 339787-NEXT; the European Union's Framework Programme for Research and Innovation Horizon 2020 (2014-2020) under the Marie Sklodowska-Curie Grant Agreements No. 674896, 690575 and 740055; the Ministerio de Economia y Competitividad of Spain under grants FIS2014-53371-C04, the Severo Ochoa Program SEV-2014-0398 and the Maria de Maetzu Program MDM-2016-0692; the GVA of Spain under grants PROMETEO/2016/120 and SEJI/2017/011; the Portuguese FCT under project PTDC/FIS-NUC/2525/2014, under project UID/FIS/04559/2013 to fund the activities of LIBPhys, and under grants PD/BD/105921/2014, SFRH/BPD/109180/2015 and SFRH/BPD/76842/2011; the U.S. Department of Energy under contracts number DE-AC02-07CH11359 (Fermi National Accelerator Laboratory), DE-AC02-06CH11357 (Argonne National Laboratory), DE-FG02-13ER42020 (Texas A&M) and DE-SC0017721 (University of Texas at Arlington); and the University of Texas at Arlington. DGD acknowledges Ramon y Cajal program (Spain) under contract number RYC-2015-18820. We also warmly acknowledge the Laboratori Nazionali del Gran Sasso (LNGS) and the Dark Side collaboration for their help with TPB coating of various parts of the NEXT-White TPC. Finally, we are grateful to the Laboratorio Subterraneo de Canfranc for hosting and supporting the NEXT experiment.Henriques, CAO.; Monteiro, CMB.; Gonzalez-Diaz, D.; Azevedo, CDR.; Freitas, EDC.; Mano, RDP.; Jorge, MR.... (2019). Electroluminescence TPCs at the thermal diffusion limit. Journal of High Energy Physics (Online). 1:1-20. https://doi.org/10.1007/JHEP01(2019)027S1201NEXT collaboration, J. Martín-Albo et al., Sensitivity of NEXT-100 to neutrinoless double beta decay, JHEP 05 (2016) 159 [ arXiv:1511.09246 ] [ INSPIRE ].T. Brunner et al., An RF-only ion-funnel for extraction from high-pressure gases, Intern. J. Mass Spectrom. 379 (2015) 110 [ INSPIRE ].PANDAX-III collaboration, J. Galan, Microbulk MicrOMEGAs for the search of 0νββ of 136 Xe in the PandaX-III experiment, 2016 JINST 11 P04024 [ arXiv:1512.09034 ] [ INSPIRE ].D. Yu. Akimov, A.A. Burenkov, V.F. Kuzichev, V.L. Morgunov and V.N. Solovev, Low background experiments with high pressure gas scintillation proportional detector, physics/9704021 [ INSPIRE ].Yu. M. Gavrilyuk et al., A technique for searching for the 2K capture in 124 Xe with a copper proportional counter, Phys. Atom. Nucl. 78 (2015) 1563 [ INSPIRE ].D.R. Nygren, Columnar recombination: a tool for nuclear recoil directional sensitivity in a xenon-based direct detection WIMP search, J. Phys. Conf. Ser. 460 (2013) 012006 [ INSPIRE ].XENON collaboration, E. Aprile et al., First Dark Matter Search Results from the XENON1T Experiment, Phys. Rev. Lett. 119 (2017) 181301 [ arXiv:1705.06655 ] [ INSPIRE ].XENON100 collaboration, E. Aprile et al., Dark Matter Results from 225 Live Days of XENON100 Data, Phys. Rev. Lett. 109 (2012) 181301 [ arXiv:1207.5988 ] [ INSPIRE ].LUX collaboration, D.S. Akerib et al., Results from a search for dark matter in the complete LUX exposure, Phys. Rev. Lett. 118 (2017) 021303 [ arXiv:1608.07648 ] [ INSPIRE ].PandaX-II collaboration, X. Cui et al., Dark Matter Results From 54-Ton-Day Exposure of PandaX-II Experiment, Phys. Rev. Lett. 119 (2017) 181302 [ arXiv:1708.06917 ] [ INSPIRE ].EXO collaboration, J.B. Albert et al., Search for Neutrinoless Double-Beta Decay with the Upgraded EXO-200 Detector, Phys. Rev. Lett. 120 (2018) 072701 [ arXiv:1707.08707 ] [ INSPIRE ].KamLAND-Zen collaboration, A. Gando et al., Search for Majorana Neutrinos near the Inverted Mass Hierarchy Region with KamLAND-Zen, Phys. Rev. Lett. 117 (2016) 082503 [ arXiv:1605.02889 ] [ INSPIRE ].XMASS collaboration, K. Abe et al., Search for two-neutrino double electron capture on 124 Xe with the XMASS-I detector, Phys. Lett. B 759 (2016) 64 [ arXiv:1510.00754 ] [ INSPIRE ].XENON collaboration, E. Aprile et al., Search for two-neutrino double electron capture of 124 Xe with XENON100, Phys. Rev. C 95 (2017) 024605 [ arXiv:1609.03354 ] [ INSPIRE ].R. Lüscher et al., Search for ββ decay in 136 Xe: new results from the Gotthard experiment, Phys. Lett. B 434 (1998) 407 [ INSPIRE ].NEXT collaboration, P. Ferrario et al., First proof of topological signature in the high pressure xenon gas TPC with electroluminescence amplification for the NEXT experiment, JHEP 01 (2016) 104 [ arXiv:1507.05902 ] [ INSPIRE ].NEXT collaboration, D. Lorca et al., Characterisation of NEXT-DEMO using xenon K α X-rays, 2014 JINST 9 P10007 [ arXiv:1407.3966 ] [ INSPIRE ].NEXT collaboration, D. González-Díaz et al., Accurate γ and MeV-electron track reconstruction with an ultra-low diffusion Xenon/TMA TPC at 10 atm, Nucl. Instrum. Meth. A 804 (2015) 8 [ arXiv:1504.03678 ] [ INSPIRE ].C.M.B. Monteiro et al., Secondary Scintillation Yield in Pure Xenon, 2007 JINST 2 P05001 [ physics/0702142 ] [ INSPIRE ].C.M.B. Monteiro, J.A.M. Lopes, J.F. C.A. Veloso and J.M.F. dos Santos, Secondary scintillation yield in pure argon, Phys. Lett. B 668 (2008) 167 [ INSPIRE ].E.D.C. Freitas et al., Secondary scintillation yield in high-pressure xenon gas for neutrinoless double beta decay (0νββ) search, Phys. Lett. B 684 (2010) 205 [ INSPIRE ].C.M.B. Monteiro et al., Secondary scintillation yield from gaseous micropattern electron multipliers in direct dark matter detection, Phys. Lett. B 677 (2009) 133 [ INSPIRE ].C.M.B. Monteiro, L.M.P. Fernandes, J.F. C.A. Veloso, C.A.B. Oliveira and J.M.F. dos Santos, Secondary scintillation yield from GEM and THGEM gaseous electron multipliers for direct dark matter search, Phys. Lett. B 714 (2012) 18 [ INSPIRE ].C. Balan et al., MicrOMEGAs operation in high pressure xenon: Charge and scintillation readout, 2011 JINST 6 P02006 [ arXiv:1009.2960 ] [ INSPIRE ].J.M.F. dos Santos et al., Development of portable gas proportional scintillation counters for x-ray spectrometry, X-Ray Spectrom. 30 (2001) 373.NEXT collaboration, J. Renner et al., Background rejection in NEXT using deep neural networks, 2017 JINST 12 T01004 [ arXiv:1609.06202 ] [ INSPIRE ].T. Himi et al., Emission spectra from Ar-Xe, Ar-Kr, Ar-N2, Ar-CH4, Ar-CO2 and Xe-N2 gas proportional scintillation counters, Nucl. Instrum. Meth. 205 (1983) 591.C.D.R. Azevedo et al., An homeopathic cure to pure Xenon large diffusion, 2016 JINST 11 C02007 [ arXiv:1511.07189 ] [ INSPIRE ].NEXT collaboration, C.A.O. Henriques et al., Secondary scintillation yield of xenon with sub-percent levels of CO 2 additive for rare-event detection, Phys. Lett. B 773 (2017) 663 [ arXiv:1704.01623 ] [ INSPIRE ].P.C.P.S. Simões, J.M.F. dos Santos and C.A.N. Conde, Driftless gas proportional scintillation counter pulse analysis using digital processing techniques, X Ray Spectrom. 30 (2001) 342.P.C.P.S. Simões et al., A new method for pulse analysis of driftless-gas proportional scintillation counters, Nucl. Instrum. Meth. A 505 (2003) 247.C.D.R. Azevedo et al., Microscopic simulation of xenon-based optical TPCs in the presence of molecular additives, Nucl. Instrum. Meth. A 877 (2018) 157 [ arXiv:1705.09481 ] [ INSPIRE ].L.M.P. Fernandes et al., Primary and secondary scintillation measurements in a xenon Gas Proportional Scintillation Counter, 2010 JINST 5 P09006 [Erratum ibid. 5 (2010) A12001] [ arXiv:1009.2719 ] [ INSPIRE ].C.M.B. Monteiro et al., An argon gas proportional scintillation counter with UV avalanche photodiode scintillation readout, IEEE Trans. Nucl. Sci. 48 (2001) 1081.J.A.M. Lopes et al., A xenon gas proportional scintillation counter with a UV-sensitive large-area avalanche photodiode, IEEE Trans. Nucl. Sci. 48 (2001) 312.D.F. Anderson et al., A large area gas scintillation proportional counter, Nucl. Instrum. Meth. 163 (1979) 125.Z. Kowalski et al., Fano factor implications from gas scintillation proportional counter measurements, Nucl. Instrum. Meth. A 279 (1989) 567.S.J.C. do Carmo et al., Experimental study of the ω-values and Fano factors of gaseous xenon and Ar-Xe mixtures for X-rays, IEEE Trans. Nucl. Sci. 55 (2008) 2637.http://magboltz.web.cern.ch/magboltz/ (accessed 14.11.2016).T.H.V.T. Dias et al., Full-energy absorption of x-ray energies near the Xe L- and K-photoionization thresholds in xenon gas detectors: Simulation and experimental results, J. Appl. Phys. 82 (1997) 2742.D. Nygren, High-pressure xenon gas electroluminescent TPC for 0νββ-decay search, Nucl. Instrum. Meth. A 603 (2009) 337 [ INSPIRE ].NEXT collaboration, V. Álvarez et al., The NEXT-100 experiment for neutrinoless double beta decay searches (Conceptual Design Report), arXiv:1106.3630 [ INSPIRE ].NEXT collaboration, V. Álvarez et al., Operation and first results of the NEXT-DEMO prototype using a silicon photomultiplier tracking array, 2013 JINST 8 P09011 [ arXiv:1306.0471 ] [ INSPIRE ]

Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

Background: Genome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into the causes of Parkinson's disease. / Methods: We did a meta-analysis of 17 datasets from Parkinson's disease GWAS available from European ancestry samples to nominate novel loci for disease risk. These datasets incorporated all available data. We then used these data to estimate heritable risk and develop predictive models of this heritability. We also used large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type, and biological pathway enrichments for the identified risk factors. Additionally, we examined shared genetic risk between Parkinson's disease and other phenotypes of interest via genetic correlations followed by Mendelian randomisation. / Findings: Between Oct 1, 2017, and Aug 9, 2018, we analysed 7·8 million single nucleotide polymorphisms in 37 688 cases, 18 618 UK Biobank proxy-cases (ie, individuals who do not have Parkinson's disease but have a first degree relative that does), and 1·4 million controls. We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16–36% of the heritable risk of Parkinson's disease depending on prevalence. Integrating methylation and expression data within a Mendelian randomisation framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested Parkinson's disease loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes (false discovery rate-adjusted p=0·0035 for intracranial volume, p=0·024 for putamen volume), smoking status (p=0·024), and educational attainment (p=0·038). Mendelian randomisation between cognitive performance and Parkinson's disease risk showed a robust association (p=8·00 × 10−7). / Interpretation: These data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, to the best of our knowledge, by revealing many additional Parkinson's disease risk loci, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified. These associations derived from European ancestry datasets will need to be followed-up with more diverse data. / Funding: The National Institute on Aging at the National Institutes of Health (USA), The Michael J Fox Foundation, and The Parkinson's Foundation (see appendix for full list of funding sources)

Edible bio-based nanostructures: delivery, absorption and potential toxicity

The development of bio-based nanostructures as nanocarriers of bioactive compounds to specific body sites has been presented as a hot topic in food, pharmaceutical and nanotechnology fields. Food and pharmaceutical industries seek to explore the huge potential of these nanostructures, once they can be entirely composed of biocompatible and non-toxic materials. At the same time, they allow the incorporation of lipophilic and hydrophilic bioactive compounds protecting them against degradation, maintaining its active and functional performance. Nevertheless, the physicochemical properties of such structures (e.g., size and charge) could change significantly their behavior in the gastrointestinal (GI) tract. The main challenges in the development of these nanostructures are the proper characterization and understanding of the processes occurring at their surface, when in contact with living systems. This is crucial to understand their delivery and absorption behavior as well as to recognize potential toxicological effects. This review will provide an insight into the recent innovations and challenges in the field of delivery via GI tract using bio-based nanostructures. Also, an overview of the approaches followed to ensure an effective deliver (e.g., avoiding physiological barriers) and to enhance stability and absorptive intestinal uptake of bioactive compounds will be provided. Information about nanostructures potential toxicity and a concise description of the in vitro and in vivo toxicity studies will also be given.Joana T. Martins, Oscar L. Ramos, Ana C. Pinheiro, Ana I. Bourbon, Helder D. Silva and Miguel A. Cerqueira (SFRH/BPD/89992/2012, SFRH/BPD/80766/2011, SFRH/BPD/101181/2014, SFRH/BD/73178/2010, SFRH/BD/81288/2011, and SFRH/BPD/72753/2010, respectively) are the recipients of a fellowship from the Fundacao para a Ciencia e Tecnologia (FCT, POPH-QREN and FSE, Portugal). The authors thank the FCT Strategic Project PEst-OE/EQB/LA0023/2013 and the project "BioInd-Biotechnology and Bioengineering for improved Industrial and Agro-Food processes," REF.NORTE-07-0124-FEDER-000028, co-funded by the Programa Operacional Regional do Norte (ON.2-O Novo Norte), QREN, FEDER. We also thank to the European Commission: BIOCAPS (316265, FP7/REGPOT-2012-2013.1) and Xunta de Galicia: Agrupamento INBIOMED (2012/273) and Grupo con potencial de crecimiento. The support of EU Cost Action FA1001 is gratefully acknowledged

Identification of Candidate Parkinson Disease Genes by Integrating Genome-Wide Association Study, Expression, and Epigenetic Data Sets

Importance Substantial genome-wide association study (GWAS) work in Parkinson disease (PD) has led to the discovery of an increasing number of loci shown reliably to be associated with increased risk of disease. Improved understanding of the underlying genes and mechanisms at these loci will be key to understanding the pathogenesis of PD. / Objective To investigate what genes and genomic processes underlie the risk of sporadic PD. / Design and Setting This genetic association study used the bioinformatic tools Coloc and transcriptome-wide association study (TWAS) to integrate PD case-control GWAS data published in 2017 with expression data (from Braineac, the Genotype-Tissue Expression [GTEx], and CommonMind) and methylation data (derived from UK Parkinson brain samples) to uncover putative gene expression and splicing mechanisms associated with PD GWAS signals. Candidate genes were further characterized using cell-type specificity, weighted gene coexpression networks, and weighted protein-protein interaction networks. / Main Outcomes and Measures It was hypothesized a priori that some genes underlying PD loci would alter PD risk through changes to expression, splicing, or methylation. Candidate genes are presented whose change in expression, splicing, or methylation are associated with risk of PD as well as the functional pathways and cell types in which these genes have an important role. / Results Gene-level analysis of expression revealed 5 genes (WDR6 [OMIM 606031], CD38 [OMIM 107270], GPNMB [OMIM 604368], RAB29 [OMIM 603949], and TMEM163 [OMIM 618978]) that replicated using both Coloc and TWAS analyses in both the GTEx and Braineac expression data sets. A further 6 genes (ZRANB3 [OMIM 615655], PCGF3 [OMIM 617543], NEK1 [OMIM 604588], NUPL2 [NCBI 11097], GALC [OMIM 606890], and CTSB [OMIM 116810]) showed evidence of disease-associated splicing effects. Cell-type specificity analysis revealed that gene expression was overall more prevalent in glial cell types compared with neurons. The weighted gene coexpression performed on the GTEx data set showed that NUPL2 is a key gene in 3 modules implicated in catabolic processes associated with protein ubiquitination and in the ubiquitin-dependent protein catabolic process in the nucleus accumbens, caudate, and putamen. TMEM163 and ZRANB3 were both important in modules in the frontal cortex and caudate, respectively, indicating regulation of signaling and cell communication. Protein interactor analysis and simulations using random networks demonstrated that the candidate genes interact significantly more with known mendelian PD and parkinsonism proteins than would be expected by chance. / Conclusions and Relevance Together, these results suggest that several candidate genes and pathways are associated with the findings observed in PD GWAS studies