Analysis of tauopathy research funding between 2006 and 2016 reveals critical gaps in research priorities.

Neurodegenerative diseases encompass a range of diagnoses, such as Alzheimer's disease and Parkinson's disease. Despite decades of advancements in understanding the neurobiology of individual diseases, this class has few disease-modifying therapeutics and a paucity of biomarkers for diagnosis or progression. However, tau protein aggregation has emerged as a potential unifying factor across several neurodegenerative diseases, which has prompted a rapid growth in tau-related funding. In spite of this growth, research funding in this area is not in line with the immense magnitude of disease burden, and drug discovery and clinical research remain underfunded. Coordinated, collaborative efforts are key to making an impact, which can and should be led by the major funding bodies within the tau space. Here we describe the development and analysis of a tau-focused neurodegeneration funding database, which captures data from 2040 grants from 2006 to 2016. This database was developed as a public resource to allow funders, researchers, and policy makers to better understand tau funding patterns and to identify key funders and potential collaborations. This database can be used in conjunction with other neurodegenerative disease databases, such as the International Alzheimer's Disease Research Portfolio to gain specific insight into tau-research funding. Over the study period, overall tau funding rose dramatically; however, changes in capital distribution also changed. Specifically, the field experienced a strong bias toward funding tau in the context of Alzheimer's disease, while at the same time generally decreasing the overall proportion of funding for basic research, treatment development, and evaluation. As funding organizations look forward, this resource can both inform future funding strategies and priority areas and identify potential collaborative efforts with complementary funding organizations.

Opportunities for epilepsy: Outcomes of the Milken Institute State of the Science Retreat.

The Milken Institute Center for Strategic Philanthropy has launched a Giving Smarter Program in Epilepsy to inform philanthropists on the state of the science for the epilepsy field, key challenges, and solutions to address them. As part of the program, the Milken Institute Center for Strategic Philanthropy hosted a retreat to identify strategic investments that would accelerate epilepsy research to ultimately improve care. The top three prioritized opportunities from the retreat were to 1) invest in data standards and analytical tool development, 2) support young investigators, and 3) promote cross-sector collaborations especially between basic scientists, preclinical researchers, clinicians, and patients.

Solution structure of the heterotrimeric complex between the interaction domains of RFX5 and RFXAP from the RFX gene regulatory complex.

The mammalian immune response is mediated by a heterotetrameric transcriptional control complex, called regulatory factor X (RFX), that regulates the expression of major histocompatibility complex class II genes. RFX comprises three proteins: RFX5 (two copies), RFXAP, and RFXB, and mutations and deletions that prevent the assembly of the RFX complex have been linked to a severe immunodeficiency disorder. Two RFX5 molecules and one RFXAP molecule assemble in the cytoplasm prior to nuclear localization, a process mediated by an N-terminal "dimerization domain" of RFX5 (RFX5(N)) and a C-terminal domain of RFXAP (RFXAP(C)). We previously presented evidence that RFXAP(C) is unstructured in the absence of RFX5(N) but adopts a regular structure in the RFX5(N)(2)-RFXAP(C) complex and that the RFX5(N)(2)-RFXAP(C) complex binds RFXB with high affinity. We now report the structure of the RFX5(N)(2)-RFXAP(C) complex, determined in solution by (15)N- and (13)C-edited NMR spectroscopy. RFX5(N) consists of a long central helix flanked by two shorter helices. The central helices of the two RFX5(N) molecules form an antiparallel coiled coil, and the flanking helices pack at the ends of the long helices in a perpendicular arrangement such that the RFX5(N) dimer is shaped like a staple. RFXAP(C) consists of two α-helices that form a V-shaped structure that packs within the RFX5(N)(2) staple. Leucine residues in the leucine-rich region of RFX5(N) (62-LYLYLQL-68) that are critical for major histocompatibility complex class II gene expression in vivo contribute to both the dimer (Leu64 and Leu68) and the RFX5(N)-RFXAP(C) interfaces (Leu62 and Leu66). The clustering of hydrophobic residues from different regions of RFXAP(C) suggests a potential binding site for RFXB.

Formation of the RFX gene regulatory complex induces folding of the interaction domain of RFXAP.

Major histocompatibility complex class II (MHCII) molecules have a central role in the mammalian adaptive immune response against infection. The level of the immune response is directly related to the concentration of MHCII molecules in the cell, which have a central role in initiating the immune response. MHCII molecules are therefore a potential target for the development of immunosuppressant drugs for the treatment of organ transplant rejection and autoimmune disease. The expression of MHCII molecules is regulated by a cell specific multiprotein complex. The RFX complex is the key DNA binding component of this complex. The RFX complex is composed of three proteins-RFX5, RFXAP, and RFXB-all of which are required for activation of expression of the MHCII genes. Little is currently known about the precise regions of the RFX proteins that are required for complex formation, or their structure. We have therefore identified the key regions of RFX5, RFXAP, and RFXB, which are required to form the RFX complex and have characterized the individual domains and the complexes they form using NMR and circular dichroism spectroscopy and isothermal titration calorimetry. Our results support a model for the assembly of the RFX complex in which the interaction between RFX5 and RFXAP promote folding of a poorly structured region ofRFXAP, which is required for high affinity binding of RFXB to the RFX5.RFXAP complex.