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Fuller H.R.,Wolfson Center for Inherited Neuromuscular Disease | Fuller H.R.,Keele University | Hurtado M.L.,Roslin Institute | Wishart T.M.,Roslin Institute | And 2 more authors.
Proteome Science | Year: 2014

Background: Idiopathic Parkinson's disease is marked by degeneration of dopamine neurons projecting from the substantia nigra to the striatum. Although proteins expressed by the target striatum can positively affect the viability and growth of dopaminergic neurons, very little is known about the molecular response of the striatum as nigro-striatal denervation progresses. Here, iTRAQ labelling and MALDI TOF/TOF mass spectrometry have been used to quantitatively compare the striatal proteome of rats before, during, and after 6-OHDA induced dopamine denervation.Results: iTRAQ analysis revealed the differential expression of 50 proteins at 3 days, 26 proteins at 7 days, and 34 proteins at 14 days post-lesioning, compared to the unlesioned striatum. While the denervated striatum showed a reduced expression of proteins associated with the loss of dopaminergic input (e.g., TH and DARPP-32), there was an increased expression of proteins associated with regeneration and growth of neurites (e.g., GFAP). In particular, the expression of guanine deaminase (GDA, cypin) - a protein known to be involved in dendritic branching - was significantly increased in the striatum at 3, 7 and 14 days post-lesioning (a finding verified by immunohistochemistry).Conclusions: Together, these findings provide evidence to suggest that the response of the normal mammalian striatum to nigro-striatal denervation includes the increased expression of proteins that may have the capacity to facilitate repair and growth of neuronal circuitry. © 2014 Fuller et al.; licensee BioMed Central Ltd. Source


Morris G.,Wolfson Center for Inherited Neuromuscular Disease
Methods in molecular biology (Clifton, N.J.) | Year: 2011

Several molecular approaches to Duchenne muscular dystrophy (DMD) therapy are at or near the point of clinical trial and usually involve attempts to replace the missing dystrophin protein. Although improved muscle function is the ultimate measure of success, assessment of dystrophin levels after therapy is essential to determine whether any improved function is a direct consequence of the treatment or, in the absence of improved function, to determine whether new dystrophin is present, though ineffective. The choice of a monoclonal antibody (mAb) to distinguish successful therapy from naturally occurring "revertant" fibres depends on which dystrophin exons are deleted in the DMD patient. Over the past 20 years, we have produced over 150 "exon-specific" mAbs, mapped them to different regions of dystrophin and made them available through the MDA Monoclonal Antibody Resource for research and for clinical trials tailored to individual patients. In this protocol, we describe the use of these mAb to monitor DMD gene therapy. Source


Holt I.,Wolfson Center for Inherited Neuromuscular Disease | Holt I.,Keele University | Gestmann I.,FEI Europe B.V. | Wright A.C.,Glyndwr University
Materials Science and Engineering C | Year: 2013

The development of scaffolds and templates is an essential aspect of tissue engineering. We show that thick (> 0.5 mm) vertically aligned carbon nanotube films, made by chemical vapour deposition, can be used as biocompatible substrates for the directional alignment of mouse muscle cells where the cells grow on the exposed sides of the films. Ultra high resolution scanning electron microscopy reveals that the films themselves consist mostly of small diameter (10 nm) multi-wall carbon nanotubes of wavy morphology with some single wall carbon nanotubes. Our findings show that for this alignment to occur the nanotubes must be in pristine condition. Mechanical wiping of the films to create directional alignment is detrimental to directional bioactivity. Larger areas for study have been formed from a composite of multiply stacked narrow strips of nanotubes wipe-transferred onto elastomer supports. These composite substrates appear to show a useful degree of alignment of the cells. © 2013 Elsevier B.V. Source


Morris G.E.,Wolfson Center for Inherited Neuromuscular Disease | Randles K.N.,Keele University
Biochemical Society Transactions | Year: 2010

The giant isoforms of nesprins 1 and 2 are emerging as important players in cellular organization, particularly in the positioning of nuclei, and possibly other organelles, within the cytoplasm. The experimental evidence suggests that nesprins also occur at the inner nuclear membrane, where they interact with the nuclear lamina. In this paper, we consider whether this is consistent with current ideas about nesprin anchorage and about mechanisms for nuclear import of membrane proteins. © The Authors Journal compilation. Source


Roper H.,Birmingham Heartlands Hospital | Quinlivan R.,Wolfson Center for Inherited Neuromuscular Disease
Archives of Disease in Childhood | Year: 2010

The diagnosis of severe type 1 spinal muscular atrophy (SMA) should be confirmed by an expert in paediatric neuromuscular disease. Invasive investigations are not usually necessary as the diagnosis is confirmed with a DNA blood test. Care thereafter should be delivered close to home by a multidisciplinary team with a clear point of access during times of crisis. The aim of care is to keep the infant as well as possible with the best possible quality of life. There are many forms of active respiratory management which can help maintain the well-being of infants with severe type 1 SMA. These include approaches to reduce the risk of infection and aspiration and appropriate techniques of airway and secretion clearance. The use of non-invasive ventilation may be helpful for some, usually less-severely affected infants, particularly to assist extubation. Long-term invasive ventilation is not recommended. Active assessment of feeding and nutrition is vital, and most babies can be managed well with nasogastric feeds. Gastrostomy may be considered for some infants, but the benefits should be carefully weighed against the risks. It is vital to share information and formulate an anticipatory care plan with the infant's parents from the point of diagnosis. Source

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