\u03b1-Synuclein pathology in Parkinson disease activates homeostatic NRF2 anti-oxidant response

Alberto Delaidelli,Poul H Sorensen,Mette Richner,Lixiang Jiang,Jens R Nyengaard,Asad Jan,Christian B Vægter,Poul H Jensen,Ida Bergholdt Jul Christiansen,Amelia Van Der Laan,Ian R Mackenzie,Nelson Ferreira

doi:10.1186/s40478-021-01209-3

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 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.

Highlights

Parkinson disease (PD) is a major neurodegenerative cause of chronic dysfunction in the subcortical somatomotor system, which is frequently compounded by nonmotor symptoms of extranigral origin [1,2,3]
IHC analyses show increased nuclear localization of phosphorylated NRF2 (p‐NRF2, serine 40 residue (S40)) in post‐mortem PD midbrain A previous neuropathological study has shown that NRF2 is abundantly detected in both cytosolic and nuclear locations in the substantia nigra (SN) region, and exhibited relatively higher localization in the neuronal nuclei in PD compared to the control brains [26]
Brainstem α‐synucleinopathy in M83 mice leads to increased phospho‐NRF2 (S40) nuclear accumulation In order to assess the significance of pathological central nervous system (CNS) aSyn accumulation in the context of the altered NRF2dependent gene response observed in PD, we examined phospho-NRF2 (S40) immunostaining in conjunction with the assessment of NRF2-responsive gene expression in the brains of transgenic M83 mice [36]

Summary

Introduction

Parkinson disease (PD) is a major neurodegenerative cause of chronic dysfunction in the subcortical somatomotor system, which is frequently compounded by nonmotor symptoms of extranigral origin [1,2,3]. In the vast majority of PD cases, the disease is of idiopathic (non-inheritable) origin, and genetic factors underlie 5–10% of clinically diagnosed PD [2]. Rare missense mutations in SNCA that result in N-terminal amino acid substitutions in aSyn, or multiplications in SNCA gene locus are recognized etiological factors in the autosomal-dominant forms of PD [2, 6, 7]. Mutations in several other genes (of autosomal-dominant or recessive inheritance) have been discovered to cause rare forms of familial PD, underscoring the complex etiology of the disease [1, 2]. The occurrence of distinct neurodegenerative lesions and progressive aSyn pathology in PD point to the selective vulnerability of specific subcortical nuclei, with relative sparing of other brain regions [4, 8, 9]

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