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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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 5

Transgenic parkin prevents neurodegeneration in RET KO mice.

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Transgenic parkin prevents neurodegeneration in RET KO mice. (A) Express...
(A) Expression of human parkin (h-parkin) in DA (TH+) neurons of the SNpc in transgenic mice crossed with parkin KO mice. Wild-type and transgenic mice but not parkin KO mice show parkin expression (scale bar: 25 μm). (B) Cell counting revealed that 93% of TH-positive cells express human parkin in the SNpc and VTA region (n = 3, 150–200 cells counted per mouse). (C and D) Stereological quantification of TH-positive neurons in (C) SNpc and (D) VTA of 12-month-old mice of the indicated genotypes (n = 3–4). (E) TH fiber density in dorsal striatum of 12-month-old mice of the indicated genotypes (n = 3–5). (F) Striatal HPLC measurements of total dopamine levels in 12-month-old mice (n = 4–7). (G) Cell soma area measurements of SNpc TH-positive neurons in 12-month-old mice (n = 3). Data are represented as mean ± SEM. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, 1-way ANOVA, Newman-Keuls post-hoc test for C–E; *P ≤ 0.05, unpaired 2-tailed t test for F and G.