title: 14-3-3 inhibition promotes dopaminergic neuron loss and 14-3-3θ overexpression promotes recovery in the MPTP mouse model of Parkinson's disease.
abstract: 14-3-3s are a highly conserved protein family that plays important roles in cell survival and interact with several proteins implicated in Parkinson's disease (PD). Disruption of 14-3-3 expression and function has been implicated in the pathogenesis of PD. We have previously shown that increasing the expression level of 14-3-3θ is protective against rotenone and 1-methyl-4-phenylpyridinium (MPP(+)) in cultured cells. Here, we extend our studies to examine the effects of 14-3-3s in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. We first investigated whether targeted nigral 14-3-3θ overexpression mediated by adeno-associated virus offers neuroprotection against MPTP-induced toxicity. 14-3-3θ overexpression using this approach did not reduce MPTP-induced dopaminergic cell loss in the substantia nigra nor the depletion of dopamine (DA) and its metabolites in the striatum at three weeks after MPTP administration. However, 14-3-3θ-overexpressing mice showed a later partial recovery in striatal DA metabolites at eight weeks after MPTP administration compared to controls, suggesting that 14-3-3θ overexpression may help in the functional recovery of those dopaminergic neurons that survive. Conversely, we investigated whether disrupting 14-3-3 function in transgenic mice expressing the pan 14-3-3 inhibitor difopein exacerbates MPTP-induced toxicity. We found that difopein expression promoted dopaminergic cell loss in response to MPTP treatment. Together, these findings suggest that 14-3-3θ overexpression promotes recovery of DA metabolites whereas 14-3-3 inhibition exacerbates neuron loss in the MPTP mouse model of PD.
authors: Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, USA.
authors: H
authors: H
authors: Ding
authors: Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, USA.
authors: R
authors: R
authors: Underwood
authors: Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, USA.
authors: N
authors: N
authors: Lavalley
authors: Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, USA. Electronic address: tyacoub@uab.edu.
authors: T A
authors: TA
authors: Yacoubian
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism*; D000256:Adenoviridae / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D020267:MPTP Poisoning / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D020127:Recovery of Function / Q000187:drug effects / Q000235:genetics; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D048948:14-3-3 Proteins; D015259:Dopamine Agents; D008164:Luminescent Proteins; D011506:Proteins; C443131:difopein; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase
keywords: 14-3-3s; MPTP; Parkinson’s disease; adeno-associated virus; dopamine; neurodegeneration