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Prion proteins as memory molecules: an hypothesis
1Institute of Enzymology, Biological Research Center, Hungarian Academy of Sciences, Budapest, Hungary.
Abstract:
Prions are infectious agents widely implicated in a variety of mammalian neurodegenerative diseases generally referred to as transmissible spongiform encephalopathies. Their infectivity is primarily associated with an aberrant conformation of a host-encoded protein, the prion protein, induced by the prion itself in an autocatalytic reaction. The physiological function of this protein is not known. In this paper we suggest that alternative conformations of the prion protein, other than its pathological scrapie state, exist and that the self-sustaining autocatalytic propagation of these states underlies its normal cellular function. In kinetic model calculations we show that the prion protein may constitute a bi-stable molecular switch that can structurally encode and stably store information. A number of cases of prion involvement in normal cellular function and ample molecular detail of pathological prion propagation are cited and correlated to substantiate the implications of this tenet. Our contention is that the prion hypothesis should be extended to a wide variety of physiological processes. We propose that prion proteins are stable determinants of phenotype, operating in diverse functions possibly including memory.
Insights
Prion proteins, implicated in neurodegenerative diseases, may have a normal cellular function. Alternative conformations could act as molecular switches, storing information and influencing phenotype, potentially including memory.
Area of Science:
- Neurobiology
- Molecular Biology
- Biochemistry
Background:
- Prions are infectious agents linked to mammalian neurodegenerative diseases, known as transmissible spongiform encephalopathies.
- Prion infectivity arises from abnormal prion protein conformations, induced by existing prions via autocatalysis.
- The normal physiological function of the prion protein remains largely unknown.
Purpose of the Study:
- To propose that alternative, non-pathological conformations of the prion protein underlie its normal cellular function.
- To investigate the potential of prion protein conformations as molecular switches for information storage.
- To extend the prion hypothesis to a broader range of physiological processes.
Main Methods:
- Theoretical modeling using kinetic calculations to assess prion protein behavior.
- Review and correlation of existing literature on prion involvement in normal cellular function.
- Analysis of molecular details concerning pathological prion propagation.
Main Results:
- Prion proteins can exist in multiple conformations beyond the pathological scrapie state.
- Kinetic modeling suggests prion proteins function as bi-stable molecular switches.
- These switches can structurally encode and stably store information.
Conclusions:
- The self-sustaining propagation of alternative prion protein states likely underlies normal cellular function.
- Prion proteins may serve as stable determinants of phenotype, with potential roles in memory.
- The prion hypothesis warrants extension to encompass diverse physiological processes.