ABSTRACT
Dopaminergic neuron degeneration is a hallmark of Parkinson's disease (PD). We previously reported that the inactivation of von HippelâLindau (VHL) alleviated dopaminergic neuron degeneration in a C. elegans model. In this study, we investigated the specific effects of VHL loss and the underlying mechanisms in mammalian PD models. For in vivo genetic inhibition of VHL, AAV-Vhl-shRNA was injected into mouse lateral ventricles. Thirty days later, the mice received MPTP for 5 days to induce PD. Behavioral experiments were conducted on D1, D3, D7, D14 and D21 after the last injection, and the mice were sacrificed on D22. We showed that knockdown of VHL in mice significantly alleviated PD-like syndromes detected in behavioral and biochemical assays. Inhibiting VHL exerted similar protective effects in MPP+-treated differentiated SH-SY5Y cells and the MPP+-induced C. elegans PD model. We further demonstrated that VHL loss-induced protection against experimental parkinsonism was independent of hypoxia-inducible factor and identified the Dishevelled-2 (DVL-2)/ß-catenin axis as the target of VHL, which was evolutionarily conserved in both C. elegans and mammals. Inhibiting the function of VHL promoted the stability of ß-catenin by reducing the ubiquitination and degradation of DVL-2. Thus, in vivo overexpression of DVL-2, mimicking VHL inactivation, protected against PD. We designed a competing peptide, Tat-DDF-2, to inhibit the interaction between VHL and DVL-2, which exhibited pharmacological potential for protection against PD in vitro and in vivo. We propose the therapeutic potential of targeting the interaction between VHL and DVL-2, which may represent a strategy to alleviate neurodegeneration associated with PD.
Subject(s)
Dishevelled Proteins , Parkinson Disease , Von Hippel-Lindau Tumor Suppressor Protein , Animals , Humans , Mice , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine , beta Catenin/metabolism , Caenorhabditis elegans/metabolism , Disease Models, Animal , Dishevelled Proteins/drug effects , Dishevelled Proteins/metabolism , Dopamine/pharmacology , Dopaminergic Neurons/metabolism , Mammals , Mice, Inbred C57BL , Neuroblastoma/metabolism , Parkinson Disease/metabolism , Parkinsonian Disorders/chemically induced , Parkinsonian Disorders/metabolism , Ubiquitination/drug effects , Ubiquitination/genetics , Von Hippel-Lindau Tumor Suppressor Protein/antagonists & inhibitors , Von Hippel-Lindau Tumor Suppressor Protein/metabolismABSTRACT
Hybrid rice breeding is the combining ability breeding. Screening hybrid rice combinations with high special combining ability (SCA) is able to breed strong superiority combinations with practical values. In this study, the genetic distances (GD) of nine three-line hybrid rice (5 CMS lines and 4 restorer lines) were examined using SSR markers. Based on yield performances of 20 hybrid crosses (5 x 4 NCII), the relationships between SCA, heterosis and GD were studied. The correlations of yield SCA with the control heterosis (r1=0.5609) and the average heterosis (r2=0.541) were significant, but not significant with GD (r=0.2143). Thus, the heterosis can be reflected by SCA; the hybrid parents selected in this study can be used to develop strong superiority combinations; but the SCA cannot be reflected by GD, which needs further study.