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Am J Neurodegener Dis 2012;1(1):15-31

Review Article
Proteolytic processing of the prion protein in health and disease

Hermann C. Altmeppen, Berta Puig, Frank Dohler, Dana K. Thurm, Clemens Falker, Susanne Krasemann, and Markus

Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Received April 25, 2012; accepted May 9, 2012; Epub May 15, 2012; published May 30, 2012

Abstract: A variety of physiological functions, not only restricted to the nervous system, are discussed for the cellular
prion protein (PrPC). A prominent, non-physiological property of PrPC is the conversion into its pathogenic isoform
(PrPSc) during fatal, transmissible, and neurodegenerative prion diseases. The prion protein is subject to
posttranslational proteolytic processing and these cleavage events have been shown i) to regulate its physiological
functions, ii) to produce biologically active fragments, and iii) to potentially influence the course of prion disease. Here,
we give an overview on the proteolytic processing under physiological and pathological conditions and critically review
what is currently known about the three main cleavage events of the prion protein, namely α-cleavage, β-cleavage, and
ectodomain shedding. The biological relevance of resulting fragments as well as controversies regarding candidate
proteases, with special emphasis on members of the A-disintegrin-and-metalloproteinase (ADAM) family, will be
discussed. In addition, we make suggestions aimed at facilitating clarity and progress in this important research field.
A better understanding of this issue will not only answer basic questions in prion biology but will likely impact research
on other neurodegenerative diseases as well. (AJND1104006)

Keywords: Prion protein, proteolytic processing, α-cleavage, β-cleavage, ectodomain shedding, ADAM10, ADAM17

Address all correspondence to:
Dr. Markus Glatzel
Institute of Neuropathology
University Medical Center Hamburg-Eppendorf
Hamburg, Germany.
E-mail: m.glatzel@uke.de