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INVESTIGATING AND MANIPULATING THE PROTEOLYTIC RELEASE OF THE PRION PROTEIN AS A PATHOPHYSIOLOGICAL MODULATOR IN NEURODEGENERATIVE PROTEINOPATHIES
Abstract
Aims
The prion protein (PrP) and the metalloprotease ADAM10 play important (patho)physiological roles. While PrP is essential for the pathogenesis of transmissible prion diseases and acts as a neuronal receptor for toxic proteins in other neurodegenerative conditions including Alzheimer`s and Parkinson`s disease, ADAM10 confers neuroprotection as it represents the major α-secretase of APP and the exclusive sheddase of PrP. We aimed to study the relevance of PrP shedding and biological functions of shed PrP (sPrP) in proteinopathies, and to identify innocuous means of manipulating this cleavage without targeting ADAM10.
Methods
We recently generated a set of cleavage site-specific antibodies for sensitive and reliable detection of sPrP in biological samples and employed multiple cell lines, organotypic slice cultures, and transgenic mice using a variety of biochemical, biophysical/structural and morphological methods.
Results
Our data suggest an inverse correlation between ADAM10 levels and prion replication. In contrast to the detrimental effects of membrane-bound PrP in proteinopathies, sPrP may block and sequester diffusible harmful protein assemblies into less toxic extracellular deposits. Notably, we reveal a substrate-specific approach to stimulate the ADAM10-mediated shedding of PrP and provide structural and mechanistic insight into how PrP-directed ligands determine the fate of cellular PrP.
Conclusions
The roles of released forms or fragments of PrP may fundamentally differ from the ones associated with their cell surface progenitor. Further studies on intrinsic functions of sPrP, on the therapeutic potential of ligand-induced PrP shedding, and on a conceivable diagnostic relevance of sPrP in body fluids are warranted and will greatly profit from site-specific antibodies.