title: Age-Related Changes of 14-3-3 Isoforms in Midbrain of A53T-SNCA Overexpressing Mice.
abstract: BACKGROUND
  Parkinson's disease (PD) is characterized by loss of midbrain dopaminergic neurons, which are affected by cytoplasmic inclusions, named Lewy pathology. The main component is alpha-synuclein (SNCA), a protein modulating SNARE-complex dependent neurotransmission. SNCA mutations trigger dominantly inherited PD variants and sporadic cases of PD via aggregation and transmission. SNCA and isoforms of the 14-3-3 family show sequence homology, protein interaction and joint aggregation, so 14-3-3 s may be key molecules of pathogenesis.
  
  
  OBJECTIVE
  We aimed to identify the relevant isoforms in midbrain and to distinguish for the first time the changes that occur very early versus those that progress with pathology.
  
  
  METHODS
  We assessed expression of the 14-3-3 family with quantitative RT-PCR and immunoblots of differential solubility fractions in mice with A53T-SNCA overexpression longitudinally at different ages.
  
  
  RESULTS
  Transcript levels showed reductions at age 3 months with increases at later ages for the beta, eta and zeta isoforms. Protein levels at age 3 months exhibited a concordant reduction only for beta, while increased insolubility was observed for epsilon and zeta. At age 18 months only the reduction of 14-3-3 beta protein remained significant. Thus, the toxic gain-of-function of alpha-synuclein leads to early transitory alterations of several 14-3-3 isoforms. When the levels of soluble 14-3-3 proteins become apparently normal during later life, increasing amounts of beta, eta and zeta mRNA are produced, possibly to compensate for protein insolubility and aggregation in a SNCA/14-3-3 complex.
  
  
  CONCLUSIONS
  These data may contribute to identify key molecular events that reflect Parkinson's disease risk and progression.
authors.forename: Nadine
authors.initials: N
authors.lastname: Brehm
authors.forename: Katrin
authors.initials: K
authors.lastname: Rau
authors.forename: Alexander
authors.initials: A
authors.lastname: Kurz
authors.forename: Suzana
authors.initials: S
authors.lastname: Gispert
authors.forename: Georg
authors.initials: G
authors.lastname: Auburger
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D000367:Age Factors; D000818:Animals; D008636:Mesencephalon / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D048948:14-3-3 Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D051844:alpha-Synuclein
keywords: Lewy body disease; biomarkers; gene expression profiles; signal transduction