Parkin cooperates with GDNF/RET signaling to prevent dopaminergic neuron degeneration
| Autor: | Durga Praveen Meka, Barbara Finckh, Anne Kathrin Müller-Rischart, Margit Miesbauer, Edgar R. Kramer, Prakash Nidadavolu, Jörg Tatzelt, Elisa Motori, Behnam Mohammadi, Konstanze F. Winklhofer, Natalie Rotermund, Anil Annamneedi, Srinivas Kumar Ponna, Mahmoud Bassal, Christian Lohr, Helia Aboutalebi |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
physiology [NF-kappa B]
physiology [Phosphatidylinositol 3-Kinases] endocrine system diseases pathology [Dopaminergic Neurons] biosynthesis [Adenosine Triphosphate] parkin protein Anxiety pathology [Parkinsonian Disorders] Parkin pathology [Mitochondria] Mice Phosphatidylinositol 3-Kinases Adenosine Triphosphate Neurotrophic factors Glial cell line-derived neurotrophic factor genetics [Glial Cell Line-Derived Neurotrophic Factor] Mice Knockout genetics [Ubiquitin-Protein Ligases] Ret protein mouse biology Dopaminergic NF-kappa B pathology [Nerve Degeneration] genetics [Proto-Oncogene Proteins c-ret] General Medicine Gdnf protein mouse Cell biology Mitochondria Substantia Nigra Proto-Oncogene Proteins c-ret genetics [Parkinsonian Disorders] Disease Progression Research Article Signal Transduction metabolism [Recombinant Fusion Proteins] medicine.medical_specialty endocrine system deficiency [Proto-Oncogene Proteins c-ret] Recombinant Fusion Proteins Ubiquitin-Protein Ligases Substantia nigra physiology [Glial Cell Line-Derived Neurotrophic Factor] Mice Transgenic deficiency [Ubiquitin-Protein Ligases] Cell Line Parkinsonian Disorders Internal medicine Dopaminergic Cell medicine Animals ddc:610 Glial Cell Line-Derived Neurotrophic Factor genetics [Anxiety] pathology [Substantia Nigra] Cell Size deficiency [Glial Cell Line-Derived Neurotrophic Factor] Pars compacta Dopaminergic Neurons nervous system diseases Endocrinology physiology [Proto-Oncogene Proteins c-ret] nervous system Rotarod Performance Test physiology [Ubiquitin-Protein Ligases] Nerve Degeneration biology.protein Exploratory Behavior |
| Zdroj: | The journal of clinical investigation 125(5), 1873-1885 (2015). doi:10.1172/JCI79300 |
| DOI: | 10.1172/JCI79300 |
| Popis: | Parkin and the glial cell line–derived neurotrophic factor (GDNF) receptor RET have both been independently linked to the dopaminergic neuron degeneration that underlies Parkinson’s disease (PD). In the present study, we demonstrate that there is genetic crosstalk between parkin and the receptor tyrosine kinase RET in two different mouse models of PD. Mice lacking both parkin and RET exhibited accelerated dopaminergic cell and axonal loss compared with parkin-deficient animals, which showed none, and RET-deficient mice, in which we found moderate degeneration. Transgenic expression of parkin protected the dopaminergic systems of aged RET-deficient mice. Downregulation of either parkin or RET in neuronal cells impaired mitochondrial function and morphology. Parkin expression restored mitochondrial function in GDNF/RET-deficient cells, while GDNF stimulation rescued mitochondrial defects in parkin-deficient cells. In both cases, improved mitochondrial function was the result of activation of the prosurvival NF-κB pathway, which was mediated by RET through the phosphoinositide-3-kinase (PI3K) pathway. Taken together, these observations indicate that parkin and the RET signaling cascade converge to control mitochondrial integrity and thereby properly maintain substantia nigra pars compacta dopaminergic neurons and their innervation in the striatum. The demonstration of crosstalk between parkin and RET highlights the interplay in the protein network that is altered in PD and suggests potential therapeutic targets and strategies to treat PD. |
| Databáze: | OpenAIRE |
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