Biomedical Sciences ETDs

Publication Date

7-1-2013

Abstract

Charcot-Marie-Tooth (CMT) Disease is a group of peripheral neuropathies affecting 1 in 2500 individuals. It is characterized by progressive sensory loss and distal muscle weakness affecting mostly the lower extremities that lead to foot deformities. More than thirty genetic loci are affected in this disease, products of which are involved in axonal trafficking. Rab7 is one such gene that gets mutated in CMT Type2B disease. To date four missense mutants of Rab7 have been identified. L129F, K157N, N161T and V162M amino acid substitutions of Rab7 occur in highly conserved regions. Rab7 is a ubiquitous protein but only the peripheral nerves get affected in this disease. This calls for an urgent need to study the pathogenesis of CMT2B disease, the awry molecular mechanisms of which remain unknown. This thesis details for the first time the impaired trafficking, altered endosomal and nuclear signaling caused by Rab7CMT2B mutants through differential interaction with effector proteins. The work provides foundation for identifying potential molecular targets for therapeutic interventions in combating this disease.

Keywords

Rab7, CMT2B disease, peripheral neuropathy, endosomal trafficking, endosomal signaling, NGF, TrkA, EGF, EGFR, p38, ERK, c-fos, Egr-1

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Advisor

Wandinger-Ness, Angela

First Committee Member (Chair)

Prossnitz, Eric R.

Second Committee Member

Caldwell, Kevin K.

Third Committee Member

Lidke, Diane S.

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