title: A53T-alpha-synuclein-overexpression in the mouse nigrostriatal pathway leads to early increase of 14-3-3 epsilon and late increase of GFAP.
abstract: Parkinson's disease (PD) is a neurodegenerative disorder frequent at old age characterized by atrophy of the nigrostriatal projection. Overexpression and A53T-mutation of the presynaptic, vesicle-associated chaperone alpha-synuclein are known to cause early-onset autosomal dominant PD. We previously generated mice with transgenic overexpression of human A53T-alpha-synuclein (A53T-SNCA) in dopaminergic substantia nigra neurons as a model of early PD. To elucidate the early and late effects of A53T-alpha-synuclein on the proteome of dopaminergic nerve terminals in the striatum, we now investigated expression profiles of young and old mice using two-dimensional fluorescence difference in gel electrophoresis (2D-DIGE) and mass spectrometry. In total, 15 proteins were upregulated and 2 downregulated. Mice before the onset of motor anomalies showed an upregulation of the spot containing 14-3-3 proteins, in particular the epsilon isoform, as well as altered levels of chaperones, vesicle trafficking and bioenergetics proteins. In old mice, the persistent upregulation of 14-3-3 proteins was aggravated by an increase of glial fibrillary acidic protein (GFAP) suggesting astrogliosis due to initial neurodegeneration. Independent immunoblots corroborated GFAP upregulation and 14-3-3 upregulation for the epsilon isoform, and also detected significant eta and gamma changes. Only for 14-3-3 epsilon a corresponding mRNA increase was observed in midbrain, suggesting it is transcribed in dopaminergic perikarya and accumulates as protein in presynapses, together with A53T-SNCA. 14-3-3 proteins associate with alpha-synuclein in vitro and in pathognomonic Lewy bodies of PD brains. They act as chaperones in signaling, dopamine synthesis and stress response. Thus, their early dysregulation probably reflects a response to alpha-synuclein toxicity.
authors.affiliation: Department of Neurology, Goethe University Medical School, 60590 Frankfurt, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kurz
authors.forename: Caroline
authors.initials: C
authors.lastname: May
authors.forename: Oliver
authors.initials: O
authors.lastname: Schmidt
authors.forename: Thorsten
authors.initials: T
authors.lastname: Müller
authors.forename: Christian
authors.initials: C
authors.lastname: Stephan
authors.forename: Helmut E
authors.initials: HE
authors.lastname: Meyer
authors.forename: Suzana
authors.initials: S
authors.lastname: Gispert
authors.forename: Georg
authors.initials: G
authors.lastname: Auburger
authors.forename: Katrin
authors.initials: K
authors.lastname: Marcus
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism*; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D013378:Substantia Nigra / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D048948:14-3-3 Proteins; D005904:Glial Fibrillary Acidic Protein; D051844:alpha-Synuclein