Date of Award

2008

Degree Type

Thesis

Department

Biological, Geological and Environmental Sciences

First Advisor

Komar, Anton

Subject Headings

Prion diseases, Prions, Slow virus diseases, Prion protein, Transmissible spongiform encephalopathies

Abstract

Transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative diseases of human, animal and yeast caused by an infectious agent designated prion. The "protein only" hypothesis proposed more than three decades ago suggests that the prions are small, infectious pathogens composed of aggregated, abnormal forms of a protein encoded in the host genome. PrPC plays primary role in neurite outgrowth, synaptic function, oxidative stress defense and long term survival of cerebellar neurons. The key event in prion disease is the conversion of the Îł-helical, cellular isoform of the prion protein to the insoluble, Îø-sheet-rich disease- causing isoform. Aggregation of misfolded prion protein into large amyloid plaques and fibrous structures is associated with neurodegeneration. TSEs attack the central nervous system leading to progressive spongiform degeneration of brain tissue. Molecular and cellular pathways leading to neurodegeneration remains still unclear. However, the recent studies suggest that pathway leading to neuronal loss include ubiquitin-proteosome and endosomal system, oxidative stress, regulated activation of complement, synaptic alterations and dendritic atrophy. The study of the unusual properties of the infectious agent and pathology of neurodegenerative disorders has been a source of excitement and arguments between the scientists. The major advances in molecular genetics and recent understanding of prion propagation and neurotoxicity allowed deep insight into prion biology

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