title: Not on the menu: autophagy-independent clearance of prions.
abstract: A common feature of neurodegenerative diseases is the accumulation of disease-specific, aggregated protein species in the nervous system. Transmissible spongiform encephalopathies are universally fatal neurodegenerative diseases involving the transconformation and aggregation of prion proteins. At the cellular level macroautophagy has been identified as an efficient pathway for the clearance of these toxic protein aggregates. Hence, recent research has focused on the pharmacological manipulation of autophagy as a potential treatment for neurodegenerative diseases. Independent of their effects on the estrogen receptor, tamoxifen and its metabolite 4-hydroxytamoxifen are well known inducers of autophagy. However, we recently reported that the ability of 4-hydroxytamoxifen to clear prion infection is independent of autophagy. In contrast, we provide a model whereby perturbation of cholesterol metabolism, and not autophagy, is the main mechanism whereby 4-hydroxytamoxifen is able to exert its anti-prion effects. Thus, while tamoxifen, a widely available pharmaceutical, may have applications in prion therapy, prions may also represent a special case and may require different pharmacological interventions than other proteinopathies.
authors.affiliation: Institut Pasteur; Unite ́ de traffic membranaire et pathogenèse; Paris, France.
authors.forename: Duncan
authors.initials: D
authors.lastname: Browman
authors.forename: Chiara
authors.initials: C
authors.lastname: Zurzolo
mesh_terms: D000818:Animals; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D018621:PrPC Proteins / Q000378:metabolism*; D018620:PrPSc Proteins / Q000378:metabolism*; D017096:Prion Diseases / Q000188:drug therapy*; D013629:Tamoxifen / Q000031:analogs & derivatives*
chemical_list: D018621:PrPC Proteins; D018620:PrPSc Proteins; D013629:Tamoxifen
keywords: 4-hydroxytamoxifen; U18666A; aggregates; autophagy; cholesterol; neurodegenerative; prion; proteinopathies; tamoxifen; trafficking
references.citation: Autophagy. 2009 Oct;5(7):1037-8
references.pmid: 19838079
references.citation: Carcinogenesis. 1996 Aug;17(8):1595-607
references.pmid: 8761415
references.citation: PLoS Pathog. 2009 May;5(5):e1000426
references.pmid: 19424437
references.citation: Folia Neuropathol. 2004;42 Suppl B:96-108
references.pmid: 16903145
references.citation: Lipids. 2009 Jun;44(6):477-87
references.pmid: 19440746
references.citation: Folia Neuropathol. 2008;46(1):1-25
references.pmid: 18368623
references.citation: Int J Biochem Cell Biol. 2004 Dec;36(12):2563-73
references.pmid: 15325593
references.citation: FEBS Lett. 2010 Jun 18;584(12):2635-45
references.pmid: 20412801
references.citation: Neuropathol Appl Neurobiol. 2010 Apr;36(2):125-32
references.pmid: 20202120
references.citation: J Biol Chem. 1999 Jul 23;274(30):20763-71
references.pmid: 10409615
references.citation: J Lipid Res. 2011 Jul;52(7):1345-51
references.pmid: 21508255
references.citation: Acta Biochim Biophys Sin (Shanghai). 2013 Jun;45(6):494-502
references.pmid: 23459558
references.citation: J Cell Sci. 2011 Feb 15;124(Pt 4):495-9
references.pmid: 21282471
references.citation: J Cell Biol. 2003 Aug 18;162(4):703-17
references.pmid: 12925711
references.citation: Cell Death Differ. 2009 Oct;16(10):1372-84
references.pmid: 19521424
references.citation: Invest Ophthalmol Vis Sci. 2012 Aug 09;53(9):5344-53
references.pmid: 22786900
references.citation: Methods Enzymol. 2009;452:1-12
references.pmid: 19200872
references.citation: Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13363-83
references.pmid: 9811807
references.citation: FASEB J. 2005 Apr;19(6):659-61
references.pmid: 15650008
references.citation: Biochem Biophys Res Commun. 2006 Sep 22;348(2):697-702
references.pmid: 16890918
references.citation: Nature. 2006 Jun 15;441(7095):880-4
references.pmid: 16625205
references.citation: Exp Mol Med. 2012 Feb 29;44(2):89-98
references.pmid: 22257884
references.citation: Curr Issues Mol Biol. 2010;12(2):87-97
references.pmid: 19767652
references.citation: Nature. 2006 Jun 15;441(7095):885-9
references.pmid: 16625204
references.citation: J Cell Sci. 2013 Mar 15;126(Pt 6):1345-54
references.pmid: 23418355
references.citation: J Neurochem. 2006 Aug;98(3):748-59
references.pmid: 16749906
references.citation: Neuroscience. 2011 Sep 15;191:107-17
references.pmid: 21396986
references.citation: Biol Pharm Bull. 2007 Apr;30(4):835-8
references.pmid: 17409533
references.citation: Front Biosci (Landmark Ed). 2011 Jan 01;16:151-68
references.pmid: 21196164
references.citation: J Virol. 1997 Nov;71(11):8821-31
references.pmid: 9343242