Exploring the role of torsina in ER stress and stress related diseases in C. elegans

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dc.contributor O'Donnell, Janis M.
dc.contributor Churchill, Perry F.
dc.contributor Marcus, Stevan
dc.contributor Standaert, David G.
dc.contributor.advisor Caldwell, Guy A.
dc.contributor.advisor Caldwell, Kim A.
dc.contributor.author Chen, Pan
dc.date.accessioned 2017-03-01T14:46:18Z
dc.date.available 2017-03-01T14:46:18Z
dc.date.issued 2011
dc.identifier.other u0015_0000001_0000695
dc.identifier.other Chen_alatus_0004D_10824
dc.identifier.uri https://ir.ua.edu/handle/123456789/1200
dc.description Electronic Thesis or Dissertation
dc.description.abstract Early-onset torsion dystonia (EOTD) is the most severe heritable form of dystonia, a human movement disorder that typically starts in childhood. A glutamic acid deletion (deltaE) in the DYT1 gene, encoding the torsinA protein, is responsible for this dominantly inherited disorder. Using an in vivo quantitative readout for the ER stress response, we evaluated the consequences of torsinA mutations in transgenic nematodes expressing variants of human torsinA. This analysis revealed that torsinA serves a protective function to maintain a homeostatic threshold against ER stress, while torsinA mutants greatly diminished this activity. In addition, using mouse embryonic fibroblasts from torsinA knockout mice, we demonstrated that loss of endogenous torsinA results in enhanced sensitivity to ER stress. Subsequent study revealed that torsinA associates with proteins in ERAD pathways, including Derlin-1, VIMP, p97 and Hrd1, to promote ER-associated degradation (ERAD) of misfolded protein, such as the mutant cystic fibrosis transmembrane conductance regulator (CFTR deltaF508). This explains the mechanism of torsinA in alleviating ER stress. Extended study found that torsinA attenuated ER stress and locomotion defect caused by a mutant superoxide dismutase 1 (G85R SOD1), which results in amyotrophic lateral sclerosis (ALS). Moreover, by applying RNA interference (RNAi) to these animals, we found a subset of genes specifically affecting the ER stress response level in torsinA expressing worms. These genetic factors reveal torsinA might be involved in the cargo trafficking from ER to Golgi and cell membranes. This study extends our understanding of the molecular mechanisms underlying EOTD.
dc.format.extent 183 p.
dc.format.medium electronic
dc.format.mimetype application/pdf
dc.language English
dc.language.iso en_US
dc.publisher University of Alabama Libraries
dc.relation.ispartof The University of Alabama Electronic Theses and Dissertations
dc.relation.ispartof The University of Alabama Libraries Digital Collections
dc.relation.hasversion born digital
dc.rights All rights reserved by the author unless otherwise indicated.
dc.subject.other Molecular biology
dc.subject.other Cellular biology
dc.subject.other Neurosciences
dc.title Exploring the role of torsina in ER stress and stress related diseases in C. elegans
dc.type thesis
dc.type text
etdms.degree.department University of Alabama. Dept. of Biological Sciences
etdms.degree.discipline Biological Sciences
etdms.degree.grantor The University of Alabama
etdms.degree.level doctoral
etdms.degree.name Ph.D.

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