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dc.contributor.advisorGillingwater, Tom
dc.contributor.advisorWishart, Tom
dc.contributor.authorMutsaers, Chantal
dc.date.accessioned2014-12-04T14:09:22Z
dc.date.available2014-12-04T14:09:22Z
dc.date.issued2014-06-28
dc.identifier.urihttp://hdl.handle.net/1842/9774
dc.description.abstractLow levels of survival motor neuron (SMN) protein cause the autosomal recessive neurodegenerative disease spinal muscular atrophy (SMA), through mechanisms that are poorly defined. SMN protein is ubiquitously expressed, however the major pathological hallmarks of SMA are focused on the neuromuscular system, including a loss of lower motor neurons in the ventral horn of the spinal cord and atrophy of skeletal muscle. At present there is no cure for SMA. Most research to date has focused on examining how low levels of SMN lead to pathological changes in motor neurons, therefore the contribution of other tissues, for example muscle, remains unclear. In this thesis I have used proteomic techniques to identify intrinsic molecular changes in muscle of SMA mice that contribute to neuromuscular pathology in SMA. I demonstrate significant disruption to the molecular composition of skeletal muscle in pre-symptomatic SMA mice, in the absence of any detectable degenerative changes in lower motor neurons and with a molecular profile distinct from that of denervated muscle. Functional cluster analysis of proteomics data and phospho-histone H2AX labelling of DNA damage revealed increased activity of cell death pathways in SMA muscle. In addition robust up-regulation of VDAC2 and down-regulation of parvalbumin was confirmed in two mouse models of SMA as well as in patient muscle biopsies. Thus intrinsic pathology of skeletal muscle is an important event in SMA. I then used proteomics to identify individual proteins in skeletal muscle of SMA that report directly on disease status. Two proteins, GRP75 and calreticulin, showed increased expression levels over time in different muscles as well as in skin samples, a more accessible tissue for biopsies in patients. Preliminary results suggest that GRP75 and calreticulin can be detected and measured in SMA patient muscle biopsies. These results show that proteomics provides a powerful platform for biomarker identification in SMA, revealing GRP75 and calreticulin as peripherally accessible potential protein biomarkers capable of reporting on disease progression in muscle as well as in skin samples. Finally I identified a role for ubiquitin-dependent pathways in regulating neuromuscular pathology in SMA. Levels of ubiquitin-like modifier activating enzyme 1 (UBA1) were reduced in spinal cord and skeletal muscle tissue of SMA mice. Dysregulation of UBA1 and subsequently the ubiquitination pathways led to the accumulation of β-catenin. I show here that pharmacological inhibition of β-catenin robustly ameliorates neuromuscular pathology in animal models of SMA. Interestingly, downstream disruption of β-catenin was restricted to the neuromuscular system in SMA mice. Pharmacological inhibition of β-catenin failed to prevent systemic pathology in organs. Thus disruption of ubiquitin homeostasis, with downstream consequences for β-catenin signalling, contributes to the pathogenesis of SMA, thereby highlighting novel therapeutic targets for this disease.en_US
dc.contributor.sponsorMedical Research Council (MRC)en_US
dc.contributor.sponsorSMA trusten_US
dc.language.isoenen_US
dc.publisherThe University of Edinburghen_US
dc.relation.hasversionMutsaers CA, Lamont DJ, Hunter G, Wishart TM, Gillingwater TH. Label-free proteomics identifies Calreticulin and GRP75/Mortalin as peripherally accessible protein biomarkers for spinal muscular atrophy. Genome Med. 2013 Oct 18;5(10):95.en_US
dc.relation.hasversionThomson SR, Nahon JE, Mutsaers CA, Thomson D, Hamilton G, Parson SH, Gillingwater TH. Morphological characteristics of motor neurons do not determine their relative susceptibility to degeneration in a mouse model of severe spinal muscular atrophy. Plos One. 2012 Dec 7(12).en_US
dc.relation.hasversionMutsaers CA, Wishart TM, Lamont DJ, Riessland M, Schreml J, Comley LH, Murray LM, Parson SH, Lochmüller H, Wirth B, Talbot K, Gillingwater TH. Reversible molecular pathology of skeletal muscle in spinal muscular atrophy. Hum Mol Genet. 2011 Nov 15;20(22):4334-44.en_US
dc.relation.hasversionComley LH, Fuller HR, Wishart TM, Mutsaers CA, Thomson D, Wright AK, Ribchester RR, Morris GE, Parson SH, Horsburgh K, Gillingwater TH. ApoE isoform-specific regulation of regeneration in the peripheral nervous system. Hum Mol Genet. 2011 Jun 15;20(12):2406-21.en_US
dc.relation.hasversionWishart TM, Huang JP, Murray LM, Lamont DJ, Mutsaers CA, Ross J, Geldsetzer P, Ansorge O, Talbot K, Parson SH, Gillingwater TH. SMN deficiency disrupts brain development in a mouse model of severe spinal muscular atrophy. Hum Mol Genet. 2010 Nov 1;19(21):4216-28.en_US
dc.relation.hasversionXu W, Berger SP, Trouw LA, de Boer HC, Schlagwein N, Mutsaers C, Daha MR, van Kooten C. Properdin binds to late apoptotic and necrotic cells independently of C3b and regulates alternative pathway complement activation. J Immunol. 2008 Jun 1;180(11):7613-21.en_US
dc.subjectSMAen_US
dc.subjectspinal muscular atrophyen_US
dc.subjectproteomicsen_US
dc.subjectdisease mechanismen_US
dc.subjectbiomarkersen_US
dc.titleMechanisms of disease pathogenesis in Spinal Muscular Atrophyen_US
dc.typeThesis or Dissertationen_US
dc.type.qualificationlevelDoctoralen_US
dc.type.qualificationnamePhD Doctor of Philosophyen_US


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