Neurodegenerative diseases are characterized by accelerated and/or inappropriate neuronal loss which is thought to be caused by genetic and environmental factors. At present predisposing factors remain unknown and effective therapies are not available for many of these diseases. However, recent work has described at least 4 pathogenic mechanisms. (1) Oxidative stress: mutations in the superoxide dismutase gene cause approximately 1% of ALS cases. (2) Neurofilament abnormalities: neurofilament overexpression causes an ALS-like phenotype in mice, while pathologically, neurofilament accumulation is observed in patients. (3) Deregulation of apoptosis: deletions in apoptosis-regulatory genes are present in spinal muscular atrophy. (4) Expansion of trinucleotide repeats---expansions are responsible for many neurodegenerative diseases including fragile X and Huntington's disease. / My work involved the investigation of these mechanisms in the pathogenesis of ALS and Parkinson's disease. Identification of molecular defects in genes regulating these pathways would provide direct evidence linking these mechanisms to neurodegeneration. Such evidence was not found. Mutations in the Mn SOD and catalase genes were absent in both disease populations. The Cu/Zn SOD gene was not mutated in Parkinson's patients. A novel allele at the NEFH KSP repeat locus was identified in Guam and Kii ALS patients but its presence in non-affected Guam and Japanese individuals eliminated it as a causative mutation. The same allele, absent in non-Asian Pacific populations, was identified in 7 affected individuals of an atypical Puerto Rican Parkinson-dystonia family. Further studies are necessary to determine whether the disease in this family is associated with this locus. / Results from the study of the SMA- and SBMA-causing mutations in ALS, revealed the presence of diagnostic errors within the ALS population. While not unexpected, the significant differences in prognosis between SMA or SBMA and ALS, make this differentiation important. Caucasian SBMA was found to be due to new mutations and not predisposing or founder chromosomes as reported in Japanese SBMA and other trinucleotide repeat diseases. / While the etiology of neurodegenerative disease is complex, my work has led to a significant increase in our understanding of this complex group of disorders. Much additional work needs to be done so that accurate diagnoses can be made and targeted effective treatments developed.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.35042 |
| Date | January 1998 |
| Creators | Parboosingh, Jillian S. |
| Contributors | Rouleau, G. A. (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Division of Experimental Medicine.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001635648, proquestno: NQ44548, Theses scanned by UMI/ProQuest. |
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