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(−/−);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 γH2AX 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 $\mu -> e \gamma$, 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 $\mu -> e \gamma$ in this model class can be within the current experimental bounds for low $\tan \beta$, but that the next generation of $\mu -> e \gamma$ 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 $\Delta {m^2}_\odot$ & $\Delta {m^2}_{atm}$ 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 $\mu \to e + \gamma$, $\mu-e$ 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