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Please use this identifier to cite or link to this item: http://hdl.handle.net/1807/32015

Title: Characterization of Peripherin Isoforms in Amyotrophic Lateral Sclerosis
Authors: McLean, Jesse Ryan
Advisor: Robertson, Janice
Department: Laboratory Medicine and Pathobiology
Keywords: Amyotrophic Lateral Sclerosis (ALS)
alternative translation
Issue Date: 17-Jan-2012
Abstract: Peripherin is a type III intermediate filament protein that is predominately expressed in the peripheral nervous system and in subsets of efferent projections in the central nervous systems. While the exact role of peripherin remains unclear, it is found upregulated after traumatic neuronal injury and in the devastating neurodegenerative disease amyotrophic lateral sclerosis (ALS). Interestingly, peripherin overexpressing transgenic mice succumb to motor neuron disease with pathological hallmarks reminiscent of those found in ALS. Pathological peripherin abnormalities occur with high frequency in both familial and sporadic forms of ALS, with peripherin found associated with the majority intracellular inclusions present within degenerating motor neuron populations. The findings of peripherin mutations in sporadic ALS have reinforced the importance of peripherin as a prospective etiological or propagative factor of disease pathogenesis. Surprisingly, inherited peripherin gene mutations have not been identified; as such, understanding the post-transcriptional mechanism at which peripherin imparts its effect(s) is considered a key goal and represents a pathological point-of-convergence for an otherwise complex, multifaceted disease. Prior to the commencement of this work, our group identified the presence of an abnormal peripherin alternative splice variant upregulated in ALS. In doing so, we consistently observed the presence of a second peripherin species of ~45 kDa on immunoblots of cell lysates derived from full-length peripherin transfections. Here, we identified this protein as a constitutively expressed isoform, termed Per-45, that arises from alternative translation and that is required for normal filament assembly: changes to the normal isoform expression pattern are associated with malformed filaments and intracellular inclusions. In lieu of the possibility of distinct peripherin intra-isoform associations, we identified isoform-specific expression and ratio changes in traumatic neuronal injury, in mouse models of motor neuron disease, and in ALS. Finally, we explored the interrelationships between peripherin isoform expression, protein aggregation, and neuritic outgrowth by linking these phenotypes with major pathogenic features associated with ALS, including in vitro models of oxidation, glutamate excitotoxicity, and neuroinflammation. Overall, this thesis provides exciting new insight into our knowledge of basic IF biology and the role of peripherin isoforms in injury and in motor neuron disease.
URI: http://hdl.handle.net/1807/32015
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