RESUMO
The orphan nuclear receptor Nurr1 is critical for the development, maintenance, and protection of midbrain dopaminergic neurons. Recently, we demonstrated that prostaglandins E1 (PGE1) and PGA1 directly bind to the ligand-binding domain (LBD) of Nurr1 and stimulate its transcriptional activation function. In this direction, here we report the transcriptional activation of Nurr1 by PGA2, a dehydrated metabolite of PGE2, through physical binding ably supported by NMR titration and crystal structure. The co-crystal structure of Nurr1-LBD bound to PGA2 revealed the covalent coupling of PGA2 with Nurr1-LBD through Cys566. PGA2 binding also induces a 21° shift of the activation function 2 (AF-2) helix H12 away from the protein core, similar to that observed in the Nurr1-LBD-PGA1 complex. We also show that PGA2 can rescue the locomotor deficits and neuronal degeneration in LRRK2 G2019S transgenic fly models.
Assuntos
Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares , Doença de Parkinson , Prostaglandinas A , Humanos , Ligantes , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Prostaglandinas A/genética , Prostaglandinas A/metabolismo , Animais Geneticamente Modificados , Drosophila , Modelos Animais de DoençasRESUMO
Mutations in LRRK2 are currently recognized as the most common monogenetic cause of Parkinsonism. The elevation of kinase activity of LRRK2 that frequently accompanies its mutations is widely thought to contribute to its toxicity. Accordingly, many groups have developed LRRK2-specific kinase inhibitors as a potential therapeutic strategy. Given that protein phosphorylation is a reversible event, we sought to elucidate the phosphatase(s) that can reverse LRRK2-mediated phosphorylation, with the view that targeting this phosphatase(s) may similarly be beneficial. Using an unbiased RNAi phosphatase screen conducted in a Drosophila LRRK2 model, we identified PP2A as a genetic modulator of LRRK2-induced neurotoxicity. Further, we also identified ribosomal S6 kinase (S6K), a target of PP2A, as a novel regulator of LRRK2 function. Finally, we showed that modulation of PP2A or S6K activities ameliorates LRRK2-associated disease phenotype in Drosophila.
Assuntos
Proteínas de Drosophila/genética , Proteínas de Drosophila/fisiologia , Drosophila melanogaster/enzimologia , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Proteína Fosfatase 2/fisiologia , Proteínas Quinases S6 Ribossômicas/fisiologia , Animais , Animais Geneticamente Modificados , Linhagem Celular , Ceramidas/farmacologia , Modelos Animais de Doenças , Proteínas de Drosophila/antagonistas & inibidores , Proteínas de Drosophila/metabolismo , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Cloridrato de Fingolimode/farmacologia , Mutação com Ganho de Função , Técnicas de Silenciamento de Genes , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Mutação de Sentido Incorreto , Fosfoproteínas Fosfatases/antagonistas & inibidores , Fosfoproteínas Fosfatases/genética , Fosfoproteínas Fosfatases/fisiologia , Fosforilação/efeitos dos fármacos , Proteína Fosfatase 2/antagonistas & inibidores , Proteína Fosfatase 2/genética , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Interferência de RNA , RNA Interferente Pequeno/genética , Proteínas Recombinantes/metabolismo , Proteínas Quinases S6 Ribossômicas/antagonistas & inibidores , Proteínas Quinases S6 Ribossômicas/genética , Proteínas Quinases S6 Ribossômicas 90-kDa/antagonistas & inibidores , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismoRESUMO
Current pharmacological strategies for Parkinson's disease (PD), the most common neurological movement disorder worldwide, are predominantly symptom relieving and are often plagued with undesirable side effects after prolonged treatment. Despite this, they remain as the mainstay treatment for PD due to the lack of better alternatives. Nutraceuticals are compounds derived from natural food sources that have certain therapeutic value and the advent of which has opened doors to the use of alternative strategies to tackle neurodegenerative diseases such as PD. Notably, nutraceuticals are able to position themselves as a "safer" strategy due to the fact that they are naturally derived compounds, therefore possibly having less side effects. Significant efforts have been put into better comprehending the role of nutraceuticals in PD, and we will look at some of them in this review. Broadly speaking, these compounds execute their positive effects via modulating signalling pathways, inhibiting oxidative stress, inflammation and apoptosis, as well as regulating mitochondrial homoeostasis. Importantly, we will highlight how a component of green tea, epigallocatechin-3-gallate (EGCG), confers neuroprotection in PD via its ability to activate AMP kinase and articulate how its beneficial effects in PD are possibly due to enhancing mitochondrial quality control.
