Spinal cord injury (SCI) is typically complicated by progressive hemorrhagic necrosis, an autodestructive process of secondary injury characterized by progressive enlargement of a hemorrhagic contusion during the first several hours after trauma. We assessed the role of Abcc8, which encodes sulfonylurea receptor 1 (SUR1), in progressive hemorrhagic necrosis. After SCI, humans and rodents exhibited similar regional and cellular patterns of up-regulation of SUR1 and Abcc8 messenger RNA. Elimination of SUR1 in Abcc8 −/− mice and in rats given antisense oligodeoxynucleotide against Abcc8 prevented progressive hemorrhagic necrosis, yielded significantly better neurological function, and resulted in lesions that were one-fourth to one-third the size of those in control animals. The beneficial effects of Abcc8 suppression were associated with prevention of oncotic (necrotic) death of capillary endothelial cells. Suppression of Abcc8 with antisense oligodeoxynucleotide after SCI presents an opportunity for reducing the devastating sequelae of SCI.* To whom correspondence should be addressed. msimard@smail.umaryland.edu.Author contributions: J.M.S. conceived the study, participated in the analysis and interpretation of the data, and wrote the manuscript. S.K.W. designed and developed the custom antibody to SUR1 and designed in situ hybridization probes for Abcc8. M.D.N. and D.L. provided human specimens and aided in analyzing histopathology. C.T. performed immunolabeling and analysis for capillary fragmentation. Z.C. isolated and cultured microvascular endothelial cells from wild-type and SUR1-null mice and performed cell death experiments. S.I. performed most of the immunolabeling and all of the measurements of lesion volume after SCI. O.T. performed all of the surgical procedures for SCI and aided in evaluating neurobehavioral function of mice and rats. J.B. supplied SUR1-null mice. V.G. aided in the design of the experiments, analysis and interpretation of the data, and neurobehavioral assessment of mice and rats and contributed to writing the final version of the manuscript.Competing interests: J.M.S. holds a U.S. patent (number 7,285,574), "A novel non-selective cation channel in neural cells and methods for treating brain swelling." J.M.S. is a member of the scientific advisory board and holds shares in Remedy Pharmaceuticals, a company that is developing small-molecule drugs targeting NC Ca-ATP channels in acute CNS injury, including traumatic brain injury, stroke, and SCI. No support, direct or indirect, was provided to J.M.S
We report a random disruption in the mouse genome that resulted in lethal paralysis in homozygous newborns. The disruption blocked expression of neurobeachin, a protein containing a BEACH (beige and Chediak-Higashi) domain implicated in synaptic vesicle trafficking and an AKAP (A-kinase anchor protein) domain linked to localization of cAMP-dependent protein kinase activity. nbea-null mice demonstrated a complete block of evoked synaptic transmission at neuromuscular junctions, whereas nerve conduction, synaptic structure, and spontaneous synaptic vesicle release were completely normal. These findings support an essential role for neurobeachin in evoked neurotransmitter release at neuromuscular junctions and suggest that it plays an important role in synaptic transmission.
Progressive multiple sclerosis (MS) will be a major area of research interest for years to come. No treatments exist and success in the field will generalise to other neurological conditions where neurodegeneration coexists with neuroinflammation. The issue is complex, and interdisciplinary approaches - uniting scientists with different competences (neurobiology, immunogenetics, etc.) and 'mindsets' (academia and industry) - will be decisive. The International Progressive MS Alliance is catalysing this process through various initiatives, the most recent of which was a meeting where scientists from academia (also outside the MS field) and from industry reviewed data and strategies to determine the next steps towards the translation of current knowledge into effective therapies.Key findings are:(i). Concerted efforts are essential to prioritise pathogenetic mechanisms according to impact on the disease and druggability.(ii). Combination therapies will probably be needed, possibly early in the disease, along with new trial designs and treatment schedules.(iii). Drug screenings are a pragmatic approach hopefully enriched by the use of neural and oligodendrocyte progenitors differentiated from induced pluripotent stem cells (iPSCs).(iv). The field of network biology will increase our ability to predict therapeutic targets.(v). Genome-wide association studies (GWAS) must try to identify variants associated with disease progression.
Background: Multiple Sclerosis (MS) is a growing global health challenge affecting nearly 3 million people. Progress has been made in the understanding and treatment of MS over the last several decades, but cures remain elusive. The National MS Society is focused on achieving cures for MS. Objectives: Cures for MS will be hastened by having a roadmap that describes knowledge gaps, milestones, and research priorities. In this report, we share the Pathways to Cures Research Roadmap and recommendations for strategies to accelerate the development of MS cures. Methods: The Roadmap was developed through engagement of scientific thought leaders and people affected by MS from North America and the United Kingdom. It also included the perspectives of over 300 people living with MS and was endorsed by many leading MS organizations. Results: The Roadmap consist of three distinct but overlapping cure pathways: (1) stopping the MS disease process, (2) restoring lost function by reversing damage and symptoms, and (3) ending MS through prevention. Better alignment and focus of global resources on high priority research questions are also recommended. Conclusions: We hope the Roadmap will inspire greater collaboration and alignment of global resources that accelerate scientific breakthroughs leading to cures for MS.
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