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@ARTICLE{Meka:137919,
author = {Meka, Durga Praveen and Müller-Rischart, Anne Kathrin and
Nidadavolu, Prakash and Mohammadi, Behnam and Motori, Elisa
and Ponna, Srinivas Kumar and Aboutalebi, Helia and Bassal,
Mahmoud and Annamneedi, Anil and Finckh, Barbara and
Miesbauer, Margit and Rotermund, Natalie and Lohr, Christian
and Tatzelt, Jörg and Winklhofer, Konstanze F and Kramer,
Edgar R},
title = {{P}arkin cooperates with {GDNF}/{RET} signaling to prevent
dopaminergic neuron degeneration.},
journal = {The journal of clinical investigation},
volume = {125},
number = {5},
issn = {0021-9738},
address = {Ann Arbor, Mich.},
publisher = {ASCJ},
reportid = {DZNE-2020-04241},
pages = {1873-1885},
year = {2015},
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.},
keywords = {Adenosine Triphosphate: biosynthesis / Animals / Anxiety:
genetics / Cell Line / Cell Size / Disease Progression /
Dopaminergic Neurons: pathology / Exploratory Behavior /
Glial Cell Line-Derived Neurotrophic Factor: deficiency /
Glial Cell Line-Derived Neurotrophic Factor: genetics /
Glial Cell Line-Derived Neurotrophic Factor: physiology /
Mice / Mice, Knockout / Mice, Transgenic / Mitochondria:
pathology / NF-kappa B: physiology / Nerve Degeneration:
pathology / Parkinsonian Disorders: genetics / Parkinsonian
Disorders: pathology / Phosphatidylinositol 3-Kinases:
physiology / Proto-Oncogene Proteins c-ret: deficiency /
Proto-Oncogene Proteins c-ret: genetics / Proto-Oncogene
Proteins c-ret: physiology / Recombinant Fusion Proteins:
metabolism / Rotarod Performance Test / Signal Transduction
/ Substantia Nigra: pathology / Ubiquitin-Protein Ligases:
deficiency / Ubiquitin-Protein Ligases: genetics /
Ubiquitin-Protein Ligases: physiology / Gdnf protein, mouse
(NLM Chemicals) / Glial Cell Line-Derived Neurotrophic
Factor (NLM Chemicals) / NF-kappa B (NLM Chemicals) /
Recombinant Fusion Proteins (NLM Chemicals) / Adenosine
Triphosphate (NLM Chemicals) / Ubiquitin-Protein Ligases
(NLM Chemicals) / parkin protein (NLM Chemicals) /
Phosphatidylinositol 3-Kinases (NLM Chemicals) /
Proto-Oncogene Proteins c-ret (NLM Chemicals) / Ret protein,
mouse (NLM Chemicals)},
cin = {AG Winklhofer},
ddc = {610},
cid = {I:(DE-2719)5000047},
pnm = {341 - Molecular Signaling (POF3-341)},
pid = {G:(DE-HGF)POF3-341},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:25822020},
pmc = {pmc:PMC4611569},
doi = {10.1172/JCI79300},
url = {https://pub.dzne.de/record/137919},
}