TY  - JOUR
AU  - Meka, Durga Praveen
AU  - Müller-Rischart, Anne Kathrin
AU  - Nidadavolu, Prakash
AU  - Mohammadi, Behnam
AU  - Motori, Elisa
AU  - Ponna, Srinivas Kumar
AU  - Aboutalebi, Helia
AU  - Bassal, Mahmoud
AU  - Annamneedi, Anil
AU  - Finckh, Barbara
AU  - Miesbauer, Margit
AU  - Rotermund, Natalie
AU  - Lohr, Christian
AU  - Tatzelt, Jörg
AU  - Winklhofer, Konstanze F
AU  - Kramer, Edgar R
TI  - Parkin cooperates with GDNF/RET signaling to prevent dopaminergic neuron degeneration.
JO  - The journal of clinical investigation
VL  - 125
IS  - 5
SN  - 0021-9738
CY  - Ann Arbor, Mich.
PB  - ASCJ
M1  - DZNE-2020-04241
SP  - 1873-1885
PY  - 2015
AB  - 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.
KW  - Adenosine Triphosphate: biosynthesis
KW  - Animals
KW  - Anxiety: genetics
KW  - Cell Line
KW  - Cell Size
KW  - Disease Progression
KW  - Dopaminergic Neurons: pathology
KW  - Exploratory Behavior
KW  - Glial Cell Line-Derived Neurotrophic Factor: deficiency
KW  - Glial Cell Line-Derived Neurotrophic Factor: genetics
KW  - Glial Cell Line-Derived Neurotrophic Factor: physiology
KW  - Mice
KW  - Mice, Knockout
KW  - Mice, Transgenic
KW  - Mitochondria: pathology
KW  - NF-kappa B: physiology
KW  - Nerve Degeneration: pathology
KW  - Parkinsonian Disorders: genetics
KW  - Parkinsonian Disorders: pathology
KW  - Phosphatidylinositol 3-Kinases: physiology
KW  - Proto-Oncogene Proteins c-ret: deficiency
KW  - Proto-Oncogene Proteins c-ret: genetics
KW  - Proto-Oncogene Proteins c-ret: physiology
KW  - Recombinant Fusion Proteins: metabolism
KW  - Rotarod Performance Test
KW  - Signal Transduction
KW  - Substantia Nigra: pathology
KW  - Ubiquitin-Protein Ligases: deficiency
KW  - Ubiquitin-Protein Ligases: genetics
KW  - Ubiquitin-Protein Ligases: physiology
KW  - Gdnf protein, mouse (NLM Chemicals)
KW  - Glial Cell Line-Derived Neurotrophic Factor (NLM Chemicals)
KW  - NF-kappa B (NLM Chemicals)
KW  - Recombinant Fusion Proteins (NLM Chemicals)
KW  - Adenosine Triphosphate (NLM Chemicals)
KW  - Ubiquitin-Protein Ligases (NLM Chemicals)
KW  - parkin protein (NLM Chemicals)
KW  - Phosphatidylinositol 3-Kinases (NLM Chemicals)
KW  - Proto-Oncogene Proteins c-ret (NLM Chemicals)
KW  - Ret protein, mouse (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:25822020
C2  - pmc:PMC4611569
DO  - DOI:10.1172/JCI79300
UR  - https://pub.dzne.de/record/137919
ER  -