Degenerating spinal motor neurons in amyotrophic lateral sclerosis (ALS) are characterized by a reduced expression of neurofilament light (NF-L) mRNA and by the presence of inclusions composed of peripherin and neurofilament (NF) proteins. This thesis examines questions related to the formation and toxicity of inclusions containing peripherin. Transfection studies demonstrated that the organization of the penpherin network is disrupted by the larger NF proteins NF-M and NF-H in context of NF-L deficiency. To further investigate the in vivo assembly of peripherin, transgenic mice overexpressing the mouse peripherin gene were generated and then bred with NF-L null mice. Mice overexpressing peripherin developed a late onset motor neuron disease characterized by the formation of peripherin inclusions and by the degeneration of motor axons in two years old mice. Remarkably, a deficiency of the NF-L protein enhanced the formation of inclusions and accelerated the onset of the peripherin-mediated disease by about 15 months. Transgenic mice overexpressing the human NF-H protein in the absence of NF-L (hH;L-/- mice) were then generated to further examine the impact of a NF-L deficiency upon the formation and toxicity of protein inclusions. These mice were characterized by the formation of large perikaryal inclusions containing peripherin and NF-H. Unlike the axonal and perikaryal inclusions formed in peripherin transgenic mice, the inclusions of hH;L-/- mice were not associated with loss spinal motor neuron, thus suggesting that the toxicity of inclusions in peripherin transgenic mice may be related to their axonal localization. Finally, a last series of experiments demonstrated that stab injuries and ischemia can also trigger the formation of peripherin inclusions in brain neurons that are normally silent for peripherin expression. The combined results suggest that peripherin inclusions may participate to the pathology of ALS and perhaps to neurodegeneration in other dis
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.38100 |
| Date | January 2001 |
| Creators | Beaulieu, Jean Martin. |
| Contributors | Julien, Jean-Pierre (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 (Department of Neurology and Neurosurgery.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001838496, proquestno: NQ77056, Theses scanned by UMI/ProQuest. |
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