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

  • Delaidelli, Alberto1, 2
  • Richner, Mette3
  • Jiang, Lixiang3
  • van der Laan, Amelia3
  • Bergholdt Jul Christiansen, Ida3
  • Ferreira, Nelson3
  • Nyengaard, Jens R.4
  • Vægter, Christian B.3
  • Jensen, Poul H.3
  • Mackenzie, Ian R.1
  • Sorensen, Poul H.1, 2
  • Jan, Asad3
  • 1 University of British Columbia, Vancouver, V6T 2B5, Canada , Vancouver (Canada)
  • 2 British Columbia Cancer Research Centre, Vancouver, BC, V5Z 1L3, Canada , Vancouver (Canada)
  • 3 Aarhus University, Ole Worms Allé 3, Aarhus C, 8000, Denmark , Aarhus C (Denmark)
  • 4 Aarhus University Hospital, Aarhus N, 8200, Denmark , Aarhus N (Denmark)
Published Article
Acta Neuropathologica Communications
Springer (Biomed Central Ltd.)
Publication Date
Jun 06, 2021
DOI: 10.1186/s40478-021-01209-3
Springer Nature


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.

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