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

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  • Alberto Delaidelli, Univ British Columbia Okanagan, University of British Columbia Okanagan, University of British Columbia
  • ,
  • Mette Richner
  • Lixiang Jiang
  • Amelia van der Laan, Centre for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus University, Aarhus, Denmark; Department of Biomedicine, Aarhus University, Aarhus, Denmark.
  • ,
  • Ida Bergholdt Jul Christiansen
  • Nelson Ferreira
  • Jens R Nyengaard
  • Christian B Vægter
  • Poul H Jensen
  • Ian R Mackenzie, Univ British Columbia Okanagan, University of British Columbia Okanagan, University of British Columbia
  • ,
  • Poul H Sorensen, Univ British Columbia Okanagan, University of British Columbia Okanagan, University of British Columbia
  • ,
  • Asad Jan

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 synucleinopathies. 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/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 the 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, expressing the mutant human A53T aSyn), which manifests 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.

Original languageEnglish
Article number105
JournalActa Neuropathologica Communications
Volume9
Issue1
Number of pages16
ISSN2051-5960
DOIs
Publication statusPublished - Jun 2021

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