Collectively, these observations suggest that a variety of factors, including increased PrP c dosage and conformation-dependent conversion of PrP c to various neurotoxic species may underlie prion disease pathology, thus providing a common framework for seemingly diverse prion disease variants. Further, results from our prior work indicate that intracellular accumulation of full-length PrP c (PrP-FL) alone suffices to induce progressive neuronal toxicity in cultured neurons and severe ataxia in mice. In addition, aggregated, non-infectious oligomeric PrP has also been shown to induce neurotoxicity. For example, mutant PrP-related familial forms of prion diseases have been identified which do not involve the PrP Sc conformation. However, genetic and experimental evidence suggest that additional factors affecting PrP conformation may similarly promote neuronal pathology. The infectious form of prion disease involves a conformation-related conversion of the cellular form of PrP (PrP c) to a mildly protease-resistant aggregated, and self-propagating species termed PrP scrapie (PrP Sc). An intriguing characteristic of prion diseases is the nature of prion, a pathogen devoid of nucleic acid. Toxic effects of prion protein (PrP) have been shown in various cellular and animal models. As observed in most adult-onset neurodegenerative diseases, neurons affected in prion diseases follow a dying back pattern of degeneration, where synaptic dysfunction and loss of neuritic connectivity represent early pathogenic events that long precede cell death. Prion diseases include a number of fatal sporadic, familial and infectious neuropathies affecting humans and other mammals.
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