Identification of altered Ras signaling and intermediate filament hyperphosphorylation in giant axonal neuropathy

dc.contributor.advisorPayne, R. Mark
dc.contributor.authorMartin, Kyle B.
dc.contributor.otherCummins, Theodore R.
dc.contributor.otherMorral, Nuria
dc.contributor.otherWek, Ronald C.
dc.date.accessioned2016-01-07T17:31:21Z
dc.date.available2016-06-02T09:30:19Z
dc.date.issued2015
dc.degree.date2015en_US
dc.degree.disciplineDepartment of Medical & Molecular Geneticsen
dc.degree.grantorIndiana Universityen_US
dc.degree.levelPh.D.en_US
dc.descriptionIndiana University-Purdue University Indianapolis (IUPUI)en_US
dc.description.abstractGiant axonal neuropathy (GAN) is a rare genetic disease that causes progressive damage to the nervous system. Neurons in GAN patients develop an abnormal organization of cytoskeletal proteins called intermediate filaments (IFs), which normally provide strength and support for the overall cell structure. The irregular IF structure in GAN patient neurons leads to a progressive loss of motor skills in children and subsequent death in adolescence. GAN is caused by reduced levels of the gigaxonin (Giga) protein. Giga functions to control the degradation of other cellular proteins, and the loss of Giga in GAN cells results in significantly elevated levels of the galectin-1 (Gal-1) protein. Gal-1 stabilizes the active form of the Ras signaling protein, which functions as a molecular switch to regulate the phosphorylation and subsequent organization of IFs. The connection between these pathways led us to propose that Giga regulates IF phosphorylation and structure by modulating Ras signaling through the degradation of Gal-1. Using GAN patient cells, we demonstrated that restoring Giga reduced Gal-1 protein levels, decreased IF phosphorylation, and reestablished normal IF organization. Similar effects of reduced IF phosphorylation and improved IF structure were also obtained in GAN cells by directly decreasing the protein levels of either Gal-1, or downstream Ras signaling proteins. Taken together, these results demonstrate that the loss of Giga induces Gal-1 mediated activation of Ras signaling, thereby leading to the increased IF phosphorylation and abnormal IF structure observed in GAN cells. Identification of aberrant Ras signaling is significant because it is the first to specify a mechanism by which the loss of Giga leads to the development of GAN and provides targets for novel drug therapies for the treatment of this currently immedicable genetic disease.en_US
dc.identifier.doi10.7912/C22S34
dc.identifier.urihttps://hdl.handle.net/1805/7935
dc.identifier.urihttp://dx.doi.org/10.7912/C2/1962
dc.language.isoen_USen_US
dc.rightsAn error occurred on the license name.
dc.rights.uriAn error occurred getting the license - uri.
dc.subjectGiant axonal neuropathyen_US
dc.subjectGigaxoninen_US
dc.subjectGalectin-1en_US
dc.subjectIntermediate filamentsen_US
dc.subjectPhosphorylationen_US
dc.subject.lcshNerves, Peripheral -- Diseases
dc.subject.lcshNeuropathy
dc.subject.lcshCykoskeletal proteins
dc.subject.lcshIntermediate filament proteins
dc.subject.lcshCytoplasmic filaments
dc.subject.lcshProteins -- Metabolism -- Disorders
dc.subject.lcshProteins -- Pathophysiology
dc.subject.lcshProteins -- Synthesis
dc.titleIdentification of altered Ras signaling and intermediate filament hyperphosphorylation in giant axonal neuropathyen_US
dc.typeThesisen
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