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Oxidative Stress-Induced Signaling Pathways Implicated in the Pathogenesis of Parkinson’s Disease

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Abstract

Parkinson’s disease is the second most common neurodegenerative movement disorder; however, its etiology remains elusive. Nevertheless, in vivo observations have concluded that oxidative stress is one of the most common causes in the pathogenesis of Parkinson’s disease. It is known that mitochondria play a crucial role in reactive oxygen species-mediated pathways, and several gene products that associate with mitochondrial function are the subject of Parkinson’s disease research. The PTEN-induced kinase 1 (PINK1) protects cells from mitochondrial dysfunction and is linked to the autosomal recessive familial form of the disease. PINK1 is a key player in many signaling pathways engaged in mitophagy, apoptosis, or microglial inflammatory response and is induced by oxidative stress. Several proteins participate in mitochondrial networks, and they are associated with PINK1. The E3 ubiquitin ligase Parkin, the protease presenilin-associated rhomboid-like serine protease, the tyrosine kinase c-Abl, the protein kinase MARK2, the protease HtrA2, and the tumor necrosis factor receptor-associated protein 1 (TRAP1) provide different steps of control in protection against oxidative stress. Furthermore, environmental toxins, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, have been identified as contributors to parkinsonism by increasing oxidative stress in dopaminergic neurons. The present review discusses the mechanisms and effects of oxidative stress, the emerging concept of the impact of environmental toxins, and a possible neuroprotective role of the antioxidant astaxanthin in various neurodegenerative disorders with particular emphasis in Parkinson’s disease.

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Abbreviations

AIMP2:

Aminoacyl tRNA synthetase complex-interacting multifunctional protein 2

AMPA:

Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid

α-syn:

Alpha synuclein

ATX:

3,3′-Dihydroxy-β,β-carotene-4,4′-dioneastaxanthin

Bcl-2:

B cell leukemia-2

CSF:

Cerebrospinal fluid

CNS:

Central nervous system

Cyt c:

Cytochrome c

DA:

Dopamine

DAT:

Dopamine transporter

ER:

Endoplasmic reticulum

ERK:

Extracellular signal-regulated kinase

FBP-1:

Fructose-1,6-bisphosphatase 1

GSH:

Glutathione

HAX1:

HS1-associated protein X-1

Hsp:

Heat-shock protein

HtrA2:

High-temperature requirement A2 protease

IκB:

Inhibitory kappa B

IL:

Interleukin

IMM:

Inner mitochondrial membrane

IMS:

Intermembrane space

JNK:

c-Jun N-terminal kinase

LBs:

Lewy bodies

LDH:

Lactate dehydrogenase

LNs:

Lewy neurites

MAPK:

Mitogen-activated protein kinase

MARK2:

Microtubule affinity-regulating kinase 2

MN:

Maneb

MPP+:

4-Phenyl-2,3-dihydropyridinium ion

MPTP:

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

mtDNA:

Mitochondrial DNA

NF-κB:

Nuclear factor kappa B

NM:

Neuromelanin

NMDA:

N-methyl-d-aspartate

NMDAR:

NMDA receptor

NOS:

Nitric oxide synthase

NPCs:

Neuronal progenitor cells

OMM:

Outer mitochondrial membrane

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

PARL:

Presenilin-associated rhomboid-like serine protease

p-α-syn:

Phosphorylated α-syn

PDZ:

Postsynaptic density protein (PSD95)/Drosophila disc large tumor suppressor (Dlg1)/zonula occludens-1 protein (Zo-1)

PI3K:

Phosphoinositide-3 kinase

PINK1:

PTEN-induced kinase 1

PKCδ:

Protein kinase C delta

PQ:

Paraquat

SAPK:

Stress-activated protein kinase

SN:

Substantia nigra

SNpc:

Substantia nigra pars compacta

SOD:

Superoxide dismutase

STAT:

Signal transducer and activator of transcription

SVZ:

Subventricular zone

TCF/LEF:

T-cell factor/lymphoid enhancer-binding factor

TNF-α:

Tumor necrosis factor alpha

TRAP1:

TNF receptor-associated protein

UPS:

Ubiquitin–proteasome system

∆Ψm:

Mitochondrial membrane potential

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  1. Laboratory of Cellular and Molecular Neurobiology, Department of Biochemistry, Hellenic Pasteur Institute, 11521, Athens, Greece

    Georgia S. Gaki

  2. Department of Biological Chemistry, University of Athens Medical School, 75, M. Asias Street, 11527, Athens, Greece

    Athanasios G. Papavassiliou

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  1. Georgia S. Gaki
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Correspondence to Athanasios G. Papavassiliou.

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Gaki, G.S., Papavassiliou, A.G. Oxidative Stress-Induced Signaling Pathways Implicated in the Pathogenesis of Parkinson’s Disease. Neuromol Med 16, 217–230 (2014). https://doi.org/10.1007/s12017-014-8294-x

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