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Shen J.,Harvard University | Shen J.,New Research Building
Neurodegenerative Diseases

Mutations in several causative genes have been linked to monogenic forms of Alzheimer's disease (AD) or Parkinson's disease (PD). To look for possible common pathogenic mechanisms underlying age-related neurodegeneration in AD and PD, we employed genetic approaches to investigate systematically the roles of these gene products (e.g. presenilins (PS) for AD; Parkin, DJ-1, PINK1 and LRRK2 for PD) in the mouse brain, especially in neural circuits that are particularly vulnerable in AD or PD. Our series of genetic studies revealed that PS play cell type-specific roles in the developing brain with the most prominent function in the maintenance of neural progenitor cells. In the adult cerebral cortex, where the pathogenesis of AD occurs, loss of PS results in progressive memory impairment and age-related neurodegeneration. Specifically, PS are involved in the regulation of long-term potentiation and NMDA receptor functions. Interestingly, our further genetic dissection in the hippocampal Schaeffer collateral pathway highlighted the importance of presynaptic PS in the activity-dependent regulation of glutamate release and long-term potentiation induction via modulation of calcium release from intracellular stores. Intriguingly, our independent genetic analysis of Parkin, DJ-1, PINK1 and LRRK2 showed a common defect in activity-dependent dopamine release caused by PD-linked mutations in these genes. Together, our genetic studies suggest that presynaptic dysfunction might be a converging early pathogenic event before neurodegeneration in AD and PD. Copyright © 2010 S. Karger AG, Basel. Source

Gladyshev V.N.,New Research Building | Zhang Y.,University of Chinese Academy of Sciences
Metal Ions in Life Sciences

Biological trace metals are needed in small quantities, but used by all living organisms. They are employed in key cellular functions in a variety of biological processes, resulting in the various degree of dependence of organisms on metals. Most effort in the field has been placed on experimental studies of metal utilization pathways and metal-dependent proteins. On the other hand, systemic level analyses of metalloproteomes (or metallomes) have been limited for most metals. In this chapter, we focus on the recent advances in comparative genomics, which provides many insights into evolution and function of metal utilization. These studies suggested that iron and zinc are widely used in biology (presumably by all organisms), whereas some other metals such as copper, molybdenum, nickel, and cobalt, show scattered occurrence in various groups of organisms. For these metals, most user proteins are well characterized and their dependence on a speci fic element is evolutionarily conserved. We also discuss evolutionary dynamics of the dependence of user proteins on different metals. Overall, comparative genomics analysis of metallomes provides a foundation for the systemic level understanding of metal utilization as well as for investigating the general features, functions, and evolutionary dynamics of metal use in the three domains of life. © Springer Science+Business Media Dordrecht 2013. Source

Venna S.,Georgetown University | Jang S.,Georgetown University | Atkins M.B.,New Research Building | Atkins M.B.,Georgetown University
Cancer Drug Discovery and Development

We are in the midst of a therapeutic revolution for patients with melanoma. This chapter reviews several topics on melanoma from epidemiologic trends, to the evolution of the surgical approach, to adjuvant treatment of melanoma, and also reviews various systemic therapies for metastatic melanoma. Each component of this chapter describes advances from a historical perspective, beginning with the first descriptions of melanoma in the literature, to the discovery of activating B-raf mutations in melanoma, and concluding with the current immune and targeted based therapies for advanced melanoma. It serves as a segue to the more detailed therapies and advances in the ensuing chapters. © Springer Science+Business Media New York 2015. Source

Raman M.,Harvard University | Sergeev M.,Harvard University | Sergeev M.,Brigham and Womens Hospital | Garnaas M.,New Research Building | And 7 more authors.
Nature Cell Biology

The AAA-ATPase VCP (also known as p97 or CDC48) uses ATP hydrolysis to 'segregate' ubiquitylated proteins from their binding partners. VCP acts through UBX-domain-containing adaptors that provide target specificity, but the targets and functions of UBXD proteins remain poorly understood. Through systematic proteomic analysis of UBXD proteins in human cells, we reveal a network of over 195 interacting proteins, implicating VCP in diverse cellular pathways. We have explored one such complex between an unstudied adaptor UBXN10 and the intraflagellar transport B (IFT-B) complex, which regulates anterograde transport into cilia. UBXN10 localizes to cilia in a VCP-dependent manner and both VCP and UBXN10 are required for ciliogenesis. Pharmacological inhibition of VCP destabilized the IFT-B complex and increased trafficking rates. Depletion of UBXN10 in zebrafish embryos causes defects in left-right asymmetry, which depends on functional cilia. This study provides a resource for exploring the landscape of UBXD proteins in biology and identifies an unexpected requirement for VCP-UBXN10 in ciliogenesis. © 2015 Macmillan Publishers Limited. Source

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