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α-Synuclein pathology in Parkinson disease activates homeostatic NRF2 anti-oxidant response

Alberto Delaidelli, Mette Richner, Lixiang Jiang, Amelia van der Laan, Ida Bergholdt Jul Christiansen, Nelson Ferreira, Jens R. Nyengaard, Christian B. Vægter, Poul H. Jensen, Ian R. Mackenzie, Poul H. Sorensen, View ORCID ProfileAsad Jan
doi: https://doi.org/10.1101/2021.04.15.439988
Alberto Delaidelli
ǂDepartment of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada;
‡British Columbia Cancer Research Centre, Vancouver, BC V5Z 1L3 Canada.
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Mette Richner
¶Danish Research Institute of Translational Neuroscience (DANDRITE)-Nordic-EMBL Partnership for Molecular Medicine, Department of Biomedicine, Aarhus University, DK-8000, Aarhus C, Denmark;
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Lixiang Jiang
¶Danish Research Institute of Translational Neuroscience (DANDRITE)-Nordic-EMBL Partnership for Molecular Medicine, Department of Biomedicine, Aarhus University, DK-8000, Aarhus C, Denmark;
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Amelia van der Laan
¶Danish Research Institute of Translational Neuroscience (DANDRITE)-Nordic-EMBL Partnership for Molecular Medicine, Department of Biomedicine, Aarhus University, DK-8000, Aarhus C, Denmark;
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Ida Bergholdt Jul Christiansen
¶Danish Research Institute of Translational Neuroscience (DANDRITE)-Nordic-EMBL Partnership for Molecular Medicine, Department of Biomedicine, Aarhus University, DK-8000, Aarhus C, Denmark;
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Nelson Ferreira
¶Danish Research Institute of Translational Neuroscience (DANDRITE)-Nordic-EMBL Partnership for Molecular Medicine, Department of Biomedicine, Aarhus University, DK-8000, Aarhus C, Denmark;
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Jens R. Nyengaard
†Core Center for Molecular Morphology, Section for Stereology and Microscopy Department of Clinical Medicine, Department of Pathology, Aarhus University Hospital, DK-8200 Aarhus N, Denmark;
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Christian B. Vægter
¶Danish Research Institute of Translational Neuroscience (DANDRITE)-Nordic-EMBL Partnership for Molecular Medicine, Department of Biomedicine, Aarhus University, DK-8000, Aarhus C, Denmark;
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Poul H. Jensen
¶Danish Research Institute of Translational Neuroscience (DANDRITE)-Nordic-EMBL Partnership for Molecular Medicine, Department of Biomedicine, Aarhus University, DK-8000, Aarhus C, Denmark;
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Ian R. Mackenzie
ǂDepartment of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada;
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Poul H. Sorensen
ǂDepartment of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada;
‡British Columbia Cancer Research Centre, Vancouver, BC V5Z 1L3 Canada.
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Asad Jan
¶Danish Research Institute of Translational Neuroscience (DANDRITE)-Nordic-EMBL Partnership for Molecular Medicine, Department of Biomedicine, Aarhus University, DK-8000, Aarhus C, Denmark;
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  • ORCID record for Asad Jan
  • For correspondence: ajan@aias.au.dk
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ABSTRACT

Circumstantial evidence points to a pathological role of alpha-synuclein (aSyn; gene symbol SNCA), conferred by aSyn misfolding and aggregation, in Parkinson disease (PD) and related synucleionpathies. Several findings in experimental models implicate perturbations in the tissue homeostatic mechanisms triggered by pathological aSyn accumulation, including impaired redox homeostasis, as significant contributors in the pathogenesis of PD. The nuclear factor erythroid 2-related factor (NRF2) is recognized as ‘the master regulator of cellular anti-oxidant response’, both under physiological as well as in pathological conditions. Using immunohistochemical analyses, we show a robust nuclear NRF2 accumulation in post-mortem PD midbrain, detected by NRF2 phosphorylation on serine residue 40 (nuclear active p-NRF2, S40). Curated gene expression analyses of four independent publicly available microarray datasets revealed considerable alterations in NRF2-responsive genes in the disease affected regions in PD, including substantia nigra, dorsal motor nucleus of vagus, locus coeruleus and globus pallidus. To further examine the putative role of pathological aSyn accumulation on nuclear NRF2 response, we employed a transgenic mouse model of synucleionopathy (M83 line, Prnp-SNCA*Ala53Thr), which manifest widespread aSyn pathology (phosphorylated aSyn; S129) in the nervous system following intramuscular inoculation of exogenous fibrillar aSyn. We observed strong immunodetection of nuclear NRF2 in neuronal populations harboring p-aSyn (S129), and found an aberrant anti-oxidant and inflammatory gene response in the affected neuraxis. Taken together, our data support the notion that pathological aSyn accumulation impairs the redox homeostasis in nervous system, and boosting neuronal anti-oxidant response is potentially a promising approach to mitigate neurodegeneration in PD and related diseases.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • https://www.ncbi.nlm.nih.gov/geo/

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Posted April 15, 2021.
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α-Synuclein pathology in Parkinson disease activates homeostatic NRF2 anti-oxidant response
Alberto Delaidelli, Mette Richner, Lixiang Jiang, Amelia van der Laan, Ida Bergholdt Jul Christiansen, Nelson Ferreira, Jens R. Nyengaard, Christian B. Vægter, Poul H. Jensen, Ian R. Mackenzie, Poul H. Sorensen, Asad Jan
bioRxiv 2021.04.15.439988; doi: https://doi.org/10.1101/2021.04.15.439988
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α-Synuclein pathology in Parkinson disease activates homeostatic NRF2 anti-oxidant response
Alberto Delaidelli, Mette Richner, Lixiang Jiang, Amelia van der Laan, Ida Bergholdt Jul Christiansen, Nelson Ferreira, Jens R. Nyengaard, Christian B. Vægter, Poul H. Jensen, Ian R. Mackenzie, Poul H. Sorensen, Asad Jan
bioRxiv 2021.04.15.439988; doi: https://doi.org/10.1101/2021.04.15.439988

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