title: The sheddase ADAM10 is a potent modulator of prion disease.
abstract: The prion protein (PrP(C)) is highly expressed in the nervous system and critically involved in prion diseases where it misfolds into pathogenic PrP(Sc). Moreover, it has been suggested as a receptor mediating neurotoxicity in common neurodegenerative proteinopathies such as Alzheimer's disease. PrP(C) is shed at the plasma membrane by the metalloprotease ADAM10, yet the impact of this on prion disease remains enigmatic. Employing conditional knockout mice, we show that depletion of ADAM10 in forebrain neurons leads to posttranslational increase of PrP(C) levels. Upon prion infection of these mice, clinical, biochemical, and morphological data reveal that lack of ADAM10 significantly reduces incubation times and increases PrP(Sc) formation. In contrast, spatiotemporal analysis indicates that absence of shedding impairs spread of prion pathology. Our data support a dual role for ADAM10-mediated shedding and highlight the role of proteolytic processing in prion disease.
authors: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Hermann C
authors: HC
authors: Altmeppen
authors: Institute of Biochemistry, Christian Albrechts University, Kiel, Germany.
authors: Johannes
authors: J
authors: Prox
authors: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Susanne
authors: S
authors: Krasemann
authors: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Berta
authors: B
authors: Puig
authors: Department of Ophthalmology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Katharina
authors: K
authors: Kruszewski
authors: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Frank
authors: F
authors: Dohler
authors: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Christian
authors: C
authors: Bernreuther
authors: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Ana
authors: A
authors: Hoxha
authors: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Luise
authors: L
authors: Linsenmeier
authors: Department of Molecular Pathology and Neuropathology, Medical University Lodz, Lodz, Poland.
authors: Beata
authors: B
authors: Sikorska
authors: Department of Molecular Pathology and Neuropathology, Medical University Lodz, Lodz, Poland.
authors: Pawel P
authors: PP
authors: Liberski
authors: Department of Ophthalmology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Udo
authors: U
authors: Bartsch
authors: Institute of Biochemistry, Christian Albrechts University, Kiel, Germany.
authors: Paul
authors: P
authors: Saftig
authors: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Markus
authors: M
authors: Glatzel
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D002154:Calpain / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018621:PrPC Proteins / Q000378:metabolism; D017096:Prion Diseases / Q000378:metabolism*; D016548:Prosencephalon / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D018621:PrPC Proteins; D053829:Amyloid Precursor Protein Secretases; D002154:Calpain; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human
keywords: ADAM10; infectious disease; microbiology; mouse; neurodegeneration; neuroscience; prion disease; proteolytic processing; shedding
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