Overexpression of Parkinson's Disease-Associated Mutation LRRK2 G2019S in Mouse Forebrain Induces Behavioral Deficits and alpha-Synuclein Pathology

Citation: Xiong, Y. L., Neifert, S., Karuppagounder, S. S., Stankowski, J. N., Lee, B. D., Grima, J. C., . . . Dawson, V. L. (2017). Overexpression of Parkinson's Disease-Associated Mutation LRRK2 G2019S in Mouse Forebrain Induces Behavioral Deficits and alpha-Synuclein Pathology. Eneuro, 4(2), 10. https://doi.org/10.1523/eneuro.0004-17.2017Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified as an unambiguous cause of late-onset, autosomal-dominant familial Parkinson's disease (PD) and LRRK2 mutations are the strongest genetic risk factor for sporadic PD known to date. A number of transgenic mice expressing wild-type or mutant LRRK2 have been described with varying degrees of LRRK2-related abnormalities and modest pathologies. None of these studies directly addressed the role of the kinase domain in the changes observed and none of the mice present with robust features of the human disease. In an attempt to address these issues, we created a conditional LRRK2 G2019S (LRRK2 GS) mutant and a functionally negative control, LRRK2 G2019S/D1994A (LRRK2 GS/DA). Expression of LRRK2 GS or LRRK2 GS/DA was conditionally controlled using the tet-off system in which the presence of tetracycline-transactivator protein (tTA) with a CAMKII alpha promoter (CAMKII alpha-tTA) induced expression of TetP-LRRK2 GS or TetP-LRRK2 GS/DA in the mouse forebrain. Overexpression of LRRK2 GS in mouse forebrain induced behavioral deficits and alpha-synuclein pathology in a kinase-dependent manner. Similar to other genetically engineered LRRK2 GS mice, there was no significant loss of dopaminergic neurons. These mice provide an important new tool to study neurobiological changes associated with the increased kinase activity from the LRRK2 G2019S mutation, which may ultimately lead to a better understanding of not only the physiologic actions of LRRK2, but also potential pathologic actions that underlie LRRK2 GS-associated PD

Global Conservation Significance of Ecuador's Yasuní National Park

Margot S. Bass is with Finding Species, Matt Finer is with Save America's Forests, Clinton N. Jenkins is with Duke University and University of Maryland, Holger Kreft is with University of California San Diego, Diego F. Cisneros-Heredia is with King's College London and Universidad San Francisco de Quito, Shawn F. McCracken is with Texas State University and the TADPOLE Organization, Nigel C. A. Pitman is with Duke University, Peter H. English is with UT Austin, Kelly Swing is with Universidad San Francisco de Quito, Gorky Villa is with Finding Species, Anthony Di Fiore is with New York University, Christian C. Voigt is with Leibniz Institute for Zoo and Wildlife Research, Thomas H. Kunz is with Boston University.Background -- The threats facing Ecuador's Yasuní National Park are emblematic of those confronting the greater western Amazon, one of the world's last high-biodiversity wilderness areas. Notably, the country's second largest untapped oil reserves—called “ITT”—lie beneath an intact, remote section of the park. The conservation significance of Yasuní may weigh heavily in upcoming state-level and international decisions, including whether to develop the oil or invest in alternatives. Methodology/Principal Findings -- We conducted the first comprehensive synthesis of biodiversity data for Yasuní. Mapping amphibian, bird, mammal, and plant distributions, we found eastern Ecuador and northern Peru to be the only regions in South America where species richness centers for all four taxonomic groups overlap. This quadruple richness center has only one viable strict protected area (IUCN levels I–IV): Yasuní. The park covers just 14% of the quadruple richness center's area, whereas active or proposed oil concessions cover 79%. Using field inventory data, we compared Yasuní's local (alpha) and landscape (gamma) diversity to other sites, in the western Amazon and globally. These analyses further suggest that Yasuní is among the most biodiverse places on Earth, with apparent world richness records for amphibians, reptiles, bats, and trees. Yasuní also protects a considerable number of threatened species and regional endemics. Conclusions/Significance -- Yasuní has outstanding global conservation significance due to its extraordinary biodiversity and potential to sustain this biodiversity in the long term because of its 1) large size and wilderness character, 2) intact large-vertebrate assemblage, 3) IUCN level-II protection status in a region lacking other strict protected areas, and 4) likelihood of maintaining wet, rainforest conditions while anticipated climate change-induced drought intensifies in the eastern Amazon. However, further oil development in Yasuní jeopardizes its conservation values. These findings form the scientific basis for policy recommendations, including stopping any new oil activities and road construction in Yasuní and creating areas off-limits to large-scale development in adjacent northern Peru.The Blue Moon Fund, the Conservation, Food & Health Foundation, and the Forrest and Frances Lattner Foundation funded MF. The US National Science Foundation (Graduate Research Fellowship Program), Texas State University-Department of Biology, and TADPOLE funded SM. The US National Science Foundation, the L.S.B. Leakey Foundation, the Wenner-Gren Foundation for Anthropological Research, and Primate Conservation, Inc. funded AD. Establishment of the Tiputini Biodiversity Station supported by the US National Science Foundation–DBI-0434875 (Thomas H. Kunz, PI, with Laura M. MacLatchy, Christopher J. Schneider, and C. Kelly Swing, Co-PIs). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Biological Sciences, School o

Grouping practices in the primary school: what influences change?

During the 1990s, there was considerable emphasis on promoting particular kinds of pupil grouping as a means of raising educational standards. This survey of 2000 primary schools explored the extent to which schools had changed their grouping practices in responses to this, the nature of the changes made and the reasons for those changes. Forty eight percent of responding schools reported that they had made no change. Twenty two percent reported changes because of the literacy hour, 2% because of the numeracy hour, 7% because of a combination of these and 21% for other reasons. Important influences on decisions about the types of grouping adopted were related to pupil learning and differentiation, teaching, the implementation of the national literacy strategy, practical issues and school self-evaluation

Long-Term Relations Among Prosocial-Media Use, Empathy, and Prosocial Behavior

Despite recent growth of research on the effects of prosocial media, processes underlying these effects are not well understood. Two studies explored theoretically relevant mediators and moderators of the effects of prosocial media on helping. Study 1 examined associations among prosocial- and violent-media use, empathy, and helping in samples from seven countries. Prosocial-media use was positively associated with helping. This effect was mediated by empathy and was similar across cultures. Study 2 explored longitudinal relations among prosocial-video-game use, violent-video-game use, empathy, and helping in a large sample of Singaporean children and adolescents measured three times across 2 years. Path analyses showed significant longitudinal effects of prosocial- and violent-video-game use on prosocial behavior through empathy. Latent-growth-curve modeling for the 2-year period revealed that change in video-game use significantly affected change in helping, and that this relationship was mediated by change in empathy

The national portfolio for postgraduate family medicine training in South Africa : a descriptive study of acceptability, educational impact, and usefulness for assessment

Background: Since 2007 a portfolio of learning has become a requirement for assessment of postgraduate family medicine training by the Colleges of Medicine of South Africa. A uniform portfolio of learning has been developed and content validity established among the eight postgraduate programmes. The aim of this study was to investigate the portfolio's acceptability, educational impact, and perceived usefulness for assessment of competence. Methods: Two structured questionnaires of 35 closed and open-ended questions were delivered to 53 family physician supervisors and 48 registrars who had used the portfolio. Categorical and nominal/ordinal data were analysed using simple descriptive statistics. The open-ended questions were analysed with ATLAS.ti software. Results: Half of registrars did not find the portfolio clear, practical or feasible. Workshops on portfolio use, learning, and supervision were supported, and brief dedicated time daily for reflection and writing. Most supervisors felt the portfolio reflected an accurate picture of learning, but just over half of registrars agreed. While the portfolio helped with reflection on learning, participants were less convinced about how it helped them plan further learning. Supervisors graded most rotations, suggesting understanding the summative aspect, while only 61% of registrars reflected on rotations, suggesting the formative aspects are not yet optimally utilised. Poor feedback, the need for protected academic time, and pressure of service delivery impacting negatively on learning. Conclusion: This first introduction of a national portfolio for postgraduate training in family medicine in South Africa faces challenges similar to those in other countries. Acceptability of the portfolio relates to a clear purpose and guide, flexible format with tools available in the workplace, and appreciating the changing educational environment from university-based to national assessments. The role of the supervisor in direct observations of the registrar and dedicated educational meetings, giving feedback and support, cannot be overemphasized

Dopaminergic Neuronal Loss, Reduced Neurite Complexity and Autophagic Abnormalities in Transgenic Mice Expressing G2019S Mutant LRRK2

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause late-onset, autosomal dominant familial Parkinson's disease (PD) and also contribute to idiopathic PD. LRRK2 mutations represent the most common cause of PD with clinical and neurochemical features that are largely indistinguishable from idiopathic disease. Currently, transgenic mice expressing wild-type or disease-causing mutants of LRRK2 have failed to produce overt neurodegeneration, although abnormalities in nigrostriatal dopaminergic neurotransmission have been observed. Here, we describe the development and characterization of transgenic mice expressing human LRRK2 bearing the familial PD mutations, R1441C and G2019S. Our study demonstrates that expression of G2019S mutant LRRK2 induces the degeneration of nigrostriatal pathway dopaminergic neurons in an age-dependent manner. In addition, we observe autophagic and mitochondrial abnormalities in the brains of aged G2019S LRRK2 mice and markedly reduced neurite complexity of cultured dopaminergic neurons. These new LRRK2 transgenic mice will provide important tools for understanding the mechanism(s) through which familial mutations precipitate neuronal degeneration and PD