title: Differential neuroprotective effects of 14-3-3 proteins in models of Parkinson's disease.
abstract: 14-3-3 proteins are important negative regulators of cell death pathways. Recent studies have revealed alterations in 14-3-3s in Parkinson's disease (PD) and the ability of 14-3-3s to interact with alpha-synuclein (α-syn), a protein central to PD pathophysiology. In a transgenic α-syn mouse model, we found reduced expression of 14-3-3θ, ε, and γ. These same isoforms prevent α-syn inclusion formation in an H4 neuroglioma cell model. Using dopaminergic cell lines stably overexpressing each 14-3-3 isoform, we found that overexpression of 14-3-3θ, ε, or γ led to resistance to both rotenone and 1-methyl-4-phenylpyridinium (MPP(+)), while other isoforms were not protective against both toxins. Inhibition of a single protective isoform, 14-3-3θ, by shRNA did not increase vulnerability to neurotoxic injury, but toxicity was enhanced by broad-based inhibition of 14-3-3 action with the peptide inhibitor difopein. Using a transgenic C. elegans model of PD, we confirmed the ability of both human 14-3-3θ and a C. elegans 14-3-3 homolog (ftt-2) to protect dopaminergic neurons from α-syn toxicity. Collectively, these data show a strong neuroprotective effect of enhanced 14-3-3 expression - particularly of the 14-3-3θ, ε, and γ isoforms - in multiple cellular and animal models of PD, and point to the potential value of these proteins in the development of neuroprotective therapies for human PD.
authors.affiliation: Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. tyacoub@uab.edu
authors.forename: T A
authors.initials: TA
authors.lastname: Yacoubian
authors.forename: S R
authors.initials: SR
authors.lastname: Slone
authors.forename: A J
authors.initials: AJ
authors.lastname: Harrington
authors.forename: S
authors.initials: S
authors.lastname: Hamamichi
authors.forename: J M
authors.initials: JM
authors.lastname: Schieltz
authors.forename: K A
authors.initials: KA
authors.lastname: Caldwell
authors.forename: G A
authors.initials: GA
authors.lastname: Caldwell
authors.forename: D G
authors.initials: DG
authors.lastname: Standaert
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity; D048948:14-3-3 Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010300:Parkinson Disease / Q000378:metabolism*; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D012402:Rotenone / Q000633:toxicity; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D048948:14-3-3 Proteins; D020033:Protein Isoforms; D011506:Proteins; D034741:RNA, Small Interfering; D051844:alpha-Synuclein; C443131:difopein; D012402:Rotenone; D015655:1-Methyl-4-phenylpyridinium