562 research outputs found
Restoration of SMN in Schwann cells reverses myelination defects and improves neuromuscular function in spinal muscular atrophy
Spinal muscular atrophy (SMA) is a neuromuscular disease caused by low levels of SMN protein, primarily affecting lower motor neurons. Recent evidence from SMA and related conditions suggests that glial cells can influence disease severity. Here, we investigated the role of glial cells in the peripheral nervous system by creating SMA mice selectively overexpressing SMN in myelinating Schwann cells (Smn(â/â);SMN2(tg/0);SMN1(SC)). Restoration of SMN protein levels restricted solely to Schwann cells reversed myelination defects, significantly improved neuromuscular function and ameliorated neuromuscular junction pathology in SMA mice. However, restoration of SMN in Schwann cells had no impact on motor neuron soma loss from the spinal cord or ongoing systemic and peripheral pathology. This study provides evidence for a defined, intrinsic contribution of glial cells to SMA disease pathogenesis and suggests that therapies designed to include Schwann cells in their target tissues are likely to be required in order to rescue myelination defects and associated disease symptoms
Systemic restoration of UBA1 ameliorates disease in spinal muscular atrophy
Acknowledgments Blood biochemistry analysis and serum analysis were performed by the Easter Bush Pathology Department, University of Edinburgh. Animal husbandry was performed by Centre for Integrative Physiology bio-research restructure technical staff, University of Edinburgh. Assistance with intravenous injections was provided by Ian Coldicott (University of Sheffield) and Hannah Shorrock (University of Edinburgh). Human blood cDNA was a gift to GH from Kathy Evans, University of Edinburgh. Imaging was performed at the IMPACT imaging facility, University of Edinburgh, with technical assistance from Anisha Kubasik-Thayil. The authors would also like to thank Lyndsay Murray for technical discussions relating to qRT-PCR analysis. This work was supported by funding from the SMA Trust and the Anatomical Society (via grants to THG); the Euan MacDonald Centre for Motor Neurone Disease Research (via grants to THG and SHP); the Wellcome Trust (via grants to EJNG and THG); Muscular Dystrophy UK (via grants to THG and CGB); a Elphinstone Scholarship from the University of Aberdeen (to SHP); and The French Muscular Dystrophy Association (via grants to CM and JC).Peer reviewedPublisher PD
Structural Insights into Recognition of MDC1 by TopBP1 in DNA Replication Checkpoint Control
SummaryActivation of the DNA replication checkpoint by the ATR kinase requires protein interactions mediated by the ATR-activating protein, TopBP1. Accumulation of TopBP1 at stalled replication forks requires the interaction of TopBP1 BRCT5 with the phosphorylated SDT repeats of the adaptor protein MDC1. Here, we present the X-ray crystal structures of the tandem BRCT4/5 domains of TopBP1 free and in complex with a MDC1 consensus pSDpT phosphopeptide. TopBP1 BRCT4/5 adopts a variant BRCT-BRCT packing interface and recognizes its target peptide in a manner distinct from that observed in previous tandem BRCT- peptide structures. The phosphate-binding pocket and positively charged residues in a variant loop in BRCT5 present an extended binding surface for the negatively charged MDC1 phosphopeptide. Mutations in this surface reduce binding affinity and recruitment of TopBP1 to ÎłH2AX foci in cells. These studies reveal a different mode of phosphopeptide binding by BRCT domains in the DNA damage response
Soft lepton-flavor violation in a multi-Higgs-doublet seesaw model
We consider the Standard Model with an arbitrary number n_H of Higgs doublets
and enlarge the lepton sector by adding to each lepton family \ell a
right-handed neutrino singlet \nu_{\ell R}. We assume that all Yukawa-coupling
matrices are diagonal, but the Majorana mass matrix M_R of the right-handed
neutrino singlets is an arbitrary symmetric matrix, thereby introducing an
explicit but soft violation of all lepton numbers. We investigate
lepton-flavor-violating processes within this model. We pay particular
attention to the large-m_R behavior of the amplitudes for these processes,
where m_R is the order of magnitude of the matrix elements of M_R. While the
amplitudes for processes like tau^- --> mu^- gamma and Z --> tau^+ mu^- drop as
1/m_R^2 for arbitrary n_H, processes like tau^- --> mu^- e^+ e^- and mu^- -->
e^- e^+ e^- obey this power law only for n_H = 1. For n_H \geq 2, on the
contrary, those amplitudes do not fall off when m_R increases, rather they
converge towards constants. This non-decoupling of the right-handed scale
occurs because of the sub-process ell^- --> ell'^- {S_b^0}^*, where S_b^0 is a
neutral scalar which subsequently decays to e^+ e^-. That sub-process has a
contribution from charged-scalar exchange which, for n_H \geq 2, does not
decrease when m_R tends to infinity. We also perform a general study of the
non-decoupling and argue that, after performing the limit m_R --> \infty and
removing the \nu_R from the Lagrangian, our model becomes a multi-Higgs-doublet
Standard Model with suppressed flavor-changing Yukawa couplings. Finally, we
show that, with the usual assumptions about the mass scales in the seesaw
mechanism, the branching ratios of all lepton-flavor-changing processes are
several orders of magnitude smaller than present experimental limits.Comment: 46 pages, 2 figures, Revte
Lepton Flavour Violation in a Class of Lopsided SO(10) Models
A class of predictive SO(10) grand unified theories with highly asymmetric
mass matrices, known as lopsided textures, has been developed to accommodate
the observed mixing in the neutrino sector. The model class effectively
determines the rate for charged lepton flavour violation, and in particular the
branching ratio for , assuming that the supersymmetric GUT
breaks directly to the constrained minimal supersymmetric standard model
(CMSSM). We find that in light of the combined constraints on the CMSSM
parameters from direct searches and from the WMAP satellite observations, the
resulting predicted rate for in this model class can be
within the current experimental bounds for low , but that the next
generation of experiments would effectively rule out this
model class if LFV is not detected.Comment: 23 page
Neutrino masses: From fantasy to facts
Theory suggests the existence of neutrino masses, but little more. Facts are
coming close to reveal our fantasy: solar and atmospheric neutrino data
strongly indicate the need for neutrino conversions, while LSND provides an
intriguing hint. The simplest ways to reconcile these data in terms of neutrino
oscillations invoke a light sterile neutrino in addition to the three active
ones. Out of the four neutrinos, two are maximally-mixed and lie at the LSND
scale, while the others are at the solar mass scale. These schemes can be
distinguished at neutral-current-sensitive solar & atmospheric neutrino
experiments. I discuss the simplest theoretical scenarios, where the lightness
of the sterile neutrino, the nearly maximal atmospheric neutrino mixing, and
the generation of & all follow
naturally from the assumed lepton-number symmetry and its breaking. Although
the most likely interpretation of the present data is in terms of
neutrino-mass-induced oscillations, one still has room for alternative
explanations, such as flavour changing neutrino interactions, with no need for
neutrino mass or mixing. Such flavour violating transitions arise in theories
with strictly massless neutrinos, and may lead to other sizeable flavour
non-conservation effects, such as , conversion in
nuclei, unaccompanied by neutrino-less double beta decay.Comment: 33 pages, latex, 16 figures. Invited Talk at Ioannina Conference,
Symmetries in Intermediate High Energy Physics and its Applications, Oct.
1998, to be published by Springer Tracts in Modern Physics. Festschrift in
Honour of John Vergados' 60th Birthda
On the massless "just-so" solution to the solar neutrino problem
We study the effect of the non-resonant, vacuum oscillation-like neutrino
flavor conversion induced by non-standard flavor changing and non-universal
flavor diagonal neutrino interactions with electrons in the sun. We have found
an acceptable fit for the combined analysis for the solar experiments total
rates, the Super-Kamiokande (SK) energy spectrum and zenith angle dependence.
Phenomenological constraints on non-standard flavor changing and non-universal
flavor diagonal neutrino interactions are considered.Comment: 4 pages, Latex, uses eps
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