title: Parkin cooperates with GDNF/RET signaling to prevent dopaminergic neuron degeneration.
abstract: 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.
authors.forename: Durga Praveen
authors.initials: DP
authors.lastname: Meka
authors.forename: Anne Kathrin
authors.initials: AK
authors.lastname: Müller-Rischart
authors.forename: Prakash
authors.initials: P
authors.lastname: Nidadavolu
authors.forename: Behnam
authors.initials: B
authors.lastname: Mohammadi
authors.forename: Elisa
authors.initials: E
authors.lastname: Motori
authors.forename: Srinivas Kumar
authors.initials: SK
authors.lastname: Ponna
authors.forename: Helia
authors.initials: H
authors.lastname: Aboutalebi
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Bassal
authors.forename: Anil
authors.initials: A
authors.lastname: Annamneedi
authors.forename: Barbara
authors.initials: B
authors.lastname: Finckh
authors.forename: Margit
authors.initials: M
authors.lastname: Miesbauer
authors.forename: Natalie
authors.initials: N
authors.lastname: Rotermund
authors.forename: Christian
authors.initials: C
authors.lastname: Lohr
authors.forename: Jörg
authors.initials: J
authors.lastname: Tatzelt
authors.forename: Konstanze F
authors.initials: KF
authors.lastname: Winklhofer
authors.forename: Edgar R
authors.initials: ER
authors.lastname: Kramer
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D001007:Anxiety / Q000235:genetics; D002460:Cell Line; D048429:Cell Size; D018450:Disease Progression; D059290:Dopaminergic Neurons / Q000473:pathology*; D005106:Exploratory Behavior; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008928:Mitochondria / Q000473:pathology; D016328:NF-kappa B / Q000502:physiology; D009410:Nerve Degeneration / Q000473:pathology*; D020734:Parkinsonian Disorders / Q000235:genetics* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D051096:Proto-Oncogene Proteins c-ret / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D045442:Rotarod Performance Test; D015398:Signal Transduction; D013378:Substantia Nigra / Q000473:pathology; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: C495040:Gdnf protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D016328:NF-kappa B; D011993:Recombinant Fusion Proteins; D000255:Adenosine Triphosphate; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D019869:Phosphatidylinositol 3-Kinases; D051096:Proto-Oncogene Proteins c-ret; C494999:Ret protein, mouse
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