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Nrf2 as a potential target for Parkinson’s disease therapy

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Abstract

Parkinson’s disease (PD) is a complex neurodegenerative disorder featuring both motor and nonmotor symptoms associated with a progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Conventionally, PD treatment options have focused on dopamine replacement and provide only symptomatic relief. However, disease-modifying therapies are still unavailable. Mechanistically, genetic and environmental factors can produce oxidative stress which has been implicated as a core contributor to the initiation and progression of PD through the degeneration of dopaminergic neurons. Importantly, nuclear factor erythroid 2–related factor 2 (Nrf2) is essential for maintaining redox homeostasis by binding to the antioxidant response element which exists in the promoter regions of most genes coding for antioxidant enzymes. Furthermore, protein kinase C, mitogen-activated protein kinases, and phosphotidylinositol 3-kinase have been implicated in the regulation of Nrf2 activity during PD. Here, we review the evidence supporting the regulation of Nrf2 through Keap1-dependent and Keap1-independent mechanisms. We also address that targeting Nrf2 may provide a therapeutic option to mitigate oxidative stress-associated PD. Finally, we discuss currently known classes of small molecule activators of Nrf2, including Nrf2-activating compounds in PD.

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Abbreviations

6-OHDA:

6-Hydroxydopamine

ARE:

Antioxidant response element

BTB:

Bric-a-brac-Tramtrack-Broad

β-TrCP:

β-Transducin repeat-containing protein

CNC-bZIP:

Cap “n” collar basic leucine zipper

CoA:

Coenzyme A

CRLs:

Cullin-ring ubiquitin ligases

DGR:

Double glycine repeat

DMF:

Dimethyl fumarate

EGCG:

Epigallocatechin gallate

ERK1/2:

Extracellular signal-regulated protein kinase 1/2

GCLc:

Catalytic subunit of glutamate cysteine ligase

GFAP:

Glial fibrillary acidic protein

GPx:

Glutathione peroxidase

GR:

Glutathione reductase

GSH:

Glutathione

GSK-3:

Glycogen synthase kinase 3

GST:

Glutathione S-transferase

HO-1:

Heme oxygenase-1

IVR:

Intervening region

Keap1:

Kelch-like ECH-associated protein 1

KO:

Knockout

LC3:

Light chain 3

Maf:

Musculoaponeurotic fibrosarcoma

MAPKs:

Mitogen-activated protein kinases

MPTP:

1-Methyl-4-phenyl-1,2,3,6- tetrahydropyridine

Neh:

Nrf2-ECH homology

NES:

Nuclear export signal

NLS:

Nuclear localization sequence

Nrf2:

Nuclear factor erythroid 2–related factor 2

PD:

Parkinson’s disease

Rbx1:

RING box protein-1

ROC1:

Regulator of cullin-1

ROS:

Reactive oxygen species

RXRα:

Retinoid X receptor α

SFN:

Sulforaphane

SN:

Substantia nigra

SOD:

Superoxide dismutase

tBHQ:

Tert-butylhydroquinone

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Funding

This work is supported by the National Natural Science Foundation of China (grants No. 81873133, 81373629, 81241107, and 81073080 to Dong M; grants No. 81673686, 81473407, 81273640, 81141117, 30973925, and 30873396 to Niu Y).

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  1. Yingcai Niu, Jing Zhang and Miaoxian Dong contributed equally to this work.

Authors and Affiliations

  1. The Institute of Medicine, Qiqihar Medical University, 333 BuKui Street, JianHua District, Qiqihar, 161006, China

    Yingcai Niu & Miaoxian Dong

  2. Department of Hematology, the First Affiliated Hospital, Harbin Medical University, Harbin, 150001, China

    Jing Zhang

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  1. Yingcai Niu
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  2. Jing Zhang
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Miaoxian Dong had the idea for the article, Yingcai Niu drafted and critically revised the work, and Jing Zhang performed the literature search.

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Niu, Y., Zhang, J. & Dong, M. Nrf2 as a potential target for Parkinson’s disease therapy. J Mol Med 99, 917–931 (2021). https://doi.org/10.1007/s00109-021-02071-5

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