RESUMEN
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.
Asunto(s)
Proteínas Dishevelled , Enfermedad de Parkinson , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau , Animales , Humanos , Ratones , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , beta Catenina/metabolismo , Caenorhabditis elegans/metabolismo , Modelos Animales de Enfermedad , Proteínas Dishevelled/efectos de los fármacos , Proteínas Dishevelled/metabolismo , Dopamina/farmacología , Neuronas Dopaminérgicas/metabolismo , Mamíferos , Ratones Endogámicos C57BL , Neuroblastoma/metabolismo , Enfermedad de Parkinson/metabolismo , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/metabolismo , Ubiquitinación/efectos de los fármacos , Ubiquitinación/genética , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/antagonistas & inhibidores , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismoRESUMEN
Parkinson's disease (PD) is one of the common complex neurodegenerative diseases and characterized by abnormal metabolic brain networks. Fibroblast growth factor 21 (FGF21), an endocrine hormone that belongs to the fibroblast growth factor superfamily, plays an extensive role in the regulation of metabolism. However, our understandings of the specific function and mechanisms of FGF21 on PD are still quite limited. Here we aimed to elucidate the actions and the underlying mechanisms of FGF21 on dopaminergic neurodegeneration using cellular and animal models of parkinsonism. To investigate the effects of FGF21 on dopaminergic neurodegeneration in vivo and in vitro, 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine models of PD were utilized, and animals were treated with recombinant FGF21 protein or FGF21 gene delivered via an adeno-associated virus. In the present study, systemic and continuous intracerebroventricular recombinant FGF21 protein administration to mice both prevented behavioral deficits, protected dopaminergic neurons against degeneration, and ameliorated α-synuclein pathology in PD models; and in vivo gene delivery of FGF21 improved PD-like symptoms and pathologies suggesting a potential implication of FGF21 in gene therapy for PD. In vitro evidence confirmed FGF21 mediated neuroprotective benefits against PD pathologies. Further, our data suggested that enhanced autophagy was involved in the FGF21 neuroprotection in PD models, and silent information regulator 2 homolog 1 may play a crucial role in molecular mechanisms underlying anti-PD activities of FGF21.