Parkin cooperates with GDNF/RET signaling to prevent dopaminergic neuron degeneration
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Parkin cooperates with GDNF/RET signaling to prevent dopaminergic neuron degeneration. / Meka, Praveen; Müller-Rischart, Anne Kathrin; Nidadavolu, Prakash; Mohammadi, Behnam; Motori, Elisa; Ponna, Srinivas Kumar; Aboutalebi, Helia; Bassal, Mahmoud; Annamneedi, Anil; Finckh, Barbara; Miesbauer, Margit; Rotermund, Natalie; Lohr, Christian; Tatzelt, Jörg; Winklhofer, Konstanze F; Kramer, Edgar R.
In: J CLIN INVEST, Vol. 125, No. 5, 05.2015, p. 1873-85.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Parkin cooperates with GDNF/RET signaling to prevent dopaminergic neuron degeneration
AU - Meka, 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
PY - 2015/5
Y1 - 2015/5
N2 - 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.
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
KW - Animals
KW - Anxiety
KW - Cell Line
KW - Cell Size
KW - Disease Progression
KW - Dopaminergic Neurons
KW - Exploratory Behavior
KW - Glial Cell Line-Derived Neurotrophic Factor
KW - Mice
KW - Mice, Knockout
KW - Mice, Transgenic
KW - Mitochondria
KW - NF-kappa B
KW - Nerve Degeneration
KW - Parkinsonian Disorders
KW - Phosphatidylinositol 3-Kinases
KW - Proto-Oncogene Proteins c-ret
KW - Recombinant Fusion Proteins
KW - Rotarod Performance Test
KW - Signal Transduction
KW - Substantia Nigra
KW - Ubiquitin-Protein Ligases
U2 - 10.1172/JCI79300
DO - 10.1172/JCI79300
M3 - SCORING: Journal article
C2 - 25822020
VL - 125
SP - 1873
EP - 1885
JO - J CLIN INVEST
JF - J CLIN INVEST
SN - 0021-9738
IS - 5
ER -