Title

Involvement of mitochondria in the pathogenesis of amyotrophic lateral sclerosis

Date of Award

2003

Availability

Article

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Molecular Cell and Developmental Biology

First Committee Member

Carlos T. Moraes, Committee Chair

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a late-onset neurodegenerative disease. Motor neurons selectively die causing severe paralysis and death. A mouse overexpressing the mutant form of human superoxide dismutase 1 (SOD1 G93A) is a useful animal model for the disease. We used this mouse model to examine the role of mitochondria in the pathogenesis of ALS. We found that the central nervous system (CNS) mitochondrial electron transport chain had a mild defect, specifically in the cytochrome c oxidase mediated respiration. The deficiency was due to the acquired toxic function of the mutant SOD1G93A, it appeared in early asymptomatic stages of the disease, and it was specific for neural tissue. We pinpointed the defect at the level of cytochrome c, and showed that cytochrome c was dissociated from the inner mitochondrial membrane in SOD1 G93A mouse CNS tissue, even in presymptomatic mice. We collected suggestive evidence that SOD1G93A protein was unable to protect cytochrome c dissociation from the inner mitochondrial membrane in the presence of mitochondrially-derived reactive oxygen species. Furthermore, we created an ALS mouse model that was transgenic for SOD1G93A and had compromised blood-brain barrier for cyclosporin A. We demonstrated that intraperitoneal cyclosporin A treatments were beneficial, suggesting that mitochondrial permeability transition may be involved in the pathogenesis of ALS. Finally, we attempted to address the controversial issue of the effects of physical exercise in the progress of ALS. We showed that a regular exercise regimen significantly prolonged the survival of SOD1G93A mice. Overall, we were able to provide evidence suggestive of mitochondrial involvement in the pathogenic processes in the ALS mouse model.

Keywords

Biology, Molecular; Biology, Neuroscience; Biology, Cell; Health Sciences, Pathology

Link to Full Text

http://access.library.miami.edu/login?url=http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3119887