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The role of TWEAK/Fn14 signaling in the MPTP-model of Parkinson’s disease

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journal contribution
posted on 2016-07-11, 14:56 authored by S. Mustafa, H. L. Martin, L. Burkly, A. Costa, L. Miguel Martins, M. Schwaninger, P. Teismann
The tumor necrosis factor like weak inducer of apoptosis (TWEAK) and its receptor, fibroblast growth factor-inducible 14 (Fn14), mediate inflammation and neuronal apoptosis in cerebral edema, ischemic stroke and multiple sclerosis. The downstream effectors and pathways linked to TWEAK–Fn14 signaling are strongly implicated in the pathology of Parkinson’s disease (PD), thus indicating a putative role for TWEAK/Fn14 signaling in PD neurodegeneration. Using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model, we aimed to determine whether genetic ablation or pharmacologic mitigation of the TWEAK protein and its Fn14 receptor affected substantia nigra and striatum Parkinsonian pathology. Changes in endogenous TWEAK protein expression were also quantified in tissue from both MPTP-treated mice and PD human samples. TWEAK protein expression was transiently increased in the striatal tissue but remained unaltered in substantia nigra tissue of MPTP-treated mice. There was also no change of TWEAK protein levels in the substantia nigra or the striatum of human PD patients as compared to matched control subjects. Mitigating the effects of endogenous TWEAK protein using neutralizing antibody did affect MPTP-mediated neurotoxicity in the substantia nigra using the sub-acute model of MPTP (30 mg/kg i.p. over five consecutive days). Neither TWEAK nor Fn14 genetic ablation led to attenuation of MPTP-toxicity in the acute model. These findings suggest that TWEAK signaling might be an aspect of MPTP-mediated neuropathology and be involved in the overall neurodegenerative pathology of PD.

Funding

This work was supported by the Wellcome Trust WT080782MF.

History

Citation

Neuroscience, 2016, 319 (5), pp. 116-122

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/MBSP Non-Medical Departments/Molecular & Cell Biology

Version

  • VoR (Version of Record)

Published in

Neuroscience

Publisher

Elsevier on nehalf of Pergamon

issn

0306-4522

eissn

1873-7544

Acceptance date

2016-01-13

Copyright date

2016

Available date

2016-07-11

Publisher version

http://www.sciencedirect.com/science/article/pii/S0306452216000622

Language

en

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