Parkin cooperates with GDNF/RET signaling to prevent dopaminergic neuron degeneration
Durga Praveen Meka, … , Konstanze F. Winklhofer, Edgar R. Kramer
Durga Praveen Meka, … , Konstanze F. Winklhofer, Edgar R. Kramer
Published March 30, 2015
Citation Information: J Clin Invest. 2015;125(5):1873-1885. https://doi.org/10.1172/JCI79300.
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Research Article Neuroscience

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

Durga Praveen Meka, Anne Kathrin Müller-Rischart, Prakash Nidadavolu, Behnam Mohammadi, Elisa Motori, Srinivas Kumar Ponna, Helia Aboutalebi, Mahmoud Bassal, Anil Annamneedi, Barbara Finckh, Margit Miesbauer, Natalie Rotermund, Christian Lohr, Jörg Tatzelt, Konstanze F. Winklhofer, Edgar R. Kramer

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Figure 1

Late-onset and SNpc-specific degeneration of DA neurons in mice lacking RET and parkin.

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Late-onset and SNpc-specific degeneration of DA neurons in mice lacking ...
(A and B) Representative images of coronal sections from 3-month-old control DCB-Cre and RET/parkin DKO mice showing loss of (A) RET and (B) parkin expression in TH-stained DA neurons of the SNpc in the RET/parkin DKO mice (scale bar: 25 μm). (C) Representative images of coronal midbrain sections from 24-month-old mice with the indicated genotypes showing DA neurons in the SNpc and VTA stained with TH antibody (scale bar: 250 μm). (D–H) Stereological quantification of TH-positive neurons in the SNpc of (D) 3- to 6-month-old (n = 3–5), (E) 12-month-old (n = 3–6), and (F) 24-month-old (n = 3–6) mice. (G) Progressive and age-dependent loss of SNpc DA neurons in RET/parkin DKO mice (n = 5–6) over time. Data were obtained from D–F. (H) TH-positive neurons were not lost in the VTA region in any of the 24-month-old mice (n = 3–6). Data are represented as mean ± SEM. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, 1-way ANOVA, Newman-Keuls post-hoc test.