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A proline to serine substitution at position 56 in the gene encoding vesicle-associated membrane protein-associated protein B (VAPB) causes some dominantly inherited familial forms of motor neuron disease including amyotrophic lateral sclerosis (ALS) type-8. VAPB is an integral endoplasmic reticulum (ER) protein whose amino-terminus projects into the cytosol. Overexpression of ALS mutant VAPBP56S disrupts ER structure but the mechanisms by which it induces disease are not properly understood. Here we show that VAPB interacts with the outer mitochondrial membrane protein, protein tyrosine phosphatase-interacting protein 51 (PTPIP51). ER and mitochondria are both stores for intracellular calcium (Ca(2+)) and Ca(2+) exchange between these organelles occurs at regions of ER that are closely apposed to mitochondria. These are termed mitochondria-associated membranes (MAM). We demonstrate that VAPB is a MAM protein and that loss of either VAPB or PTPIP51 perturbs uptake of Ca(2+) by mitochondria following release from ER stores. Finally, we demonstrate that VAPBP56S has altered binding to PTPIP51 and increases Ca(2+) uptake by mitochondria following release from ER stores. Damage to ER, mitochondria and Ca(2+) homeostasis are all seen in ALS and we discuss the implications of our findings in this context.
Pubmed ID: 22131369
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The Wellcome Trust is the largest charity in the UK. We fund innovative biomedical research, in the UK and internationally, spending over 600 million each year to support the brightest scientists with the best ideas. The Wellcome Trust is an independent charity funding research to improve human and animal health. Established in 1936 and with an endowment of around 13 billion, it is the UK's largest non-governmental source of funds for biomedical research. What we do We spend over 600 million every year both in the UK and internationally achieving our mission. Funding We support many different kinds of research and activities with the ultimate aim of protecting and improving human and animal health. This support is not restricted to UK researchers - we devote significant funding to international research too. Biomedical science Our biomedical science funding enables the investigation of health and disease in humans and animals. This includes funding for scientists, clinicians and veterinarians at different career stages. Technology transfer Our technology transfer funding supports the development of innovative, early-stage projects with potential medical applications. Medical humanities Our medical humanities funding supports research into biomedical ethics and the history of medicine. Public engagement Our public engagement funding promotes interest, excitement and debate around science and society. Capital funding Our capital funding is for large-scale construction or refurbishment projects in the UK that support science, public engagement, medical history, or the activities of learned societies. Strategic awards Our Strategic Awards provide flexible funding that adds value to excellent research groups. Managing a grant This area contains information and resources to help you manage a grant once it has been awarded, from the grant-start certificate to the end-of-grant report and beyond. Education Resources Teaching and education Resources to help promote contemporary science in the curriculum and to enable young people to engage with biomedical science. Tree of Life Darwin200 Big Picture Science Learning Centres Scientific animations Creative Encounters Courses and conferences Trust-run conferences, courses and workshops for scientists, historians, ethicists, social scientists, teachers, healthcare professionals and policymakers, held in the UK and overseas. Advanced Courses Scientific conferences Conference centres Retreats History of medicine Biomedical ethics Biomedical resources Tools, databases and information to support different areas of biomedical research, including genomics, post-genomics and developmental biology. Animal research Genomics Model organisms Microorganisms Post-genomics Tissues Researcher support Support and advice for all kinds of engagement activities to help you communicate your work in the most effective and rewarding way possible. About researcher support National opportunities Regional opportunities Highlights Publications Browse a wealth of publications covering all aspects of the work we fund. Wellcome Trust websites Explore a range of sites covering key biomedical topics and our public engagement activities.
View all literature mentionsIt is now widely known that animals share many genes with humans and can suffer from the same diseases, for example diabetes or deafness. Investigating these diseases in animals can provide vital leads to understanding both their causes and ways to treat them in humans. This approach to medical research lies at the heart of work at the MRC Mammalian Genetics Unit (MGU) at Harwell in Oxfordshire. In 1995 the MRC Radiobiology Unit was reconstituted to form two new units, the Radiation and Genome Stability Unit and the MGU. These opened in January 1996, together with the UK Mouse Genome Centre which is now part of MGU, making MRC Harwell a unique campus for multi-disciplinary genetics research. Since MGU's Director Steve Brown took the reins in 1996, the unit has dramatically expanded its scientific scope and increased its personnel from 40 to over 100. It now has 13 research programs encompassing molecular genetics, genomics, genetic manipulation and data analysis at all levels, from single genes to the whole genome. With a combination of cutting-edge facilities and expertise unrivaled in Europe, MGU Harwell has become firmly established as one of the world's leading academic centres for mouse genetics.
View all literature mentionsOne of the main institutions of the European Union, its job is to represent and uphold the interests of the EU as a whole. It drafts proposals for new European laws. It manages the day-to-day business of implementing EU policies and spending EU funds. The 28 Commissioners, one from each EU member country, provide the Commission''s political leadership during their 5-year term. Each Commissioner is assigned responsibility for specific policy areas by the President. The Commission oversees and implements EU policies by: * proposing new laws to Parliament and the Council * managing the EU''s budget and allocating funding * enforcing EU law (together with the Court of Justice) * representing the EU internationally, for example, by negotiating agreements between the EU and other countries. The Commission is based in Brussels and Luxembourg and has offices (representations) in every EU country and delegations in capital cities around the world.
View all literature mentionsSoftware tool for automated microscope acquisition, device control, and image analysis. Used for integrating dissimilar fluorescent microscope hardware and peripherals into a single custom workstation, while providing all the tools needed to perform analysis of acquired images. Offers user friendly application modules for analysis such as cell signaling, cell counting, and protein expression.
View all literature mentionsCell line HEK293 is a Transformed cell line with a species of origin Homo sapiens (Human)
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