Affiliations: Department of Neurology, Exp. Neurology, Goethe University Medical School, Theodor Stern Kai, Frankfurt am Main, Germany
Correspondence to: Prof. Georg Auburger, Exp. Neurology, Building 89, Goethe University Medical School, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany. Tel.: +49 69 6301 7428; Fax: +49 69 6301 7142; [email protected]
Note:  Equal contribution.
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.
Keywords: Lewy body disease, gene expression profiles, signal transduction, biomarkers