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Neurotoxicity Research

, Volume 27, Issue 3, pp 328–354 | Cite as

Neurotoxin Mechanisms and Processes Relevant to Parkinson’s Disease: An Update

  • Juan Segura-AguilarEmail author
  • Richard M. Kostrzewa
Article

Abstract

The molecular mechanism responsible for degenerative process in the nigrostriatal dopaminergic system in Parkinson’s disease (PD) remains unknown. One major advance in this field has been the discovery of several genes associated to familial PD, including alpha synuclein, parkin, LRRK2, etc., thereby providing important insight toward basic research approaches. There is an consensus in neurodegenerative research that mitochon dria dysfunction, protein degradation dysfunction, aggregation of alpha synuclein to neurotoxic oligomers, oxidative and endoplasmic reticulum stress, and neuroinflammation are involved in degeneration of the neuromelanin-containing dopaminergic neurons that are lost in the disease. An update of the mechanisms relating to neurotoxins that are used to produce preclinical models of Parkinson´s disease is presented. 6-Hydroxydopamine, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and rotenone have been the most wisely used neurotoxins to delve into mechanisms involved in the loss of dopaminergic neurons containing neuromelanin. Neurotoxins generated from dopamine oxidation during neuromelanin formation are likewise reviewed, as this pathway replicates neurotoxin-induced cellular oxidative stress, inactivation of key proteins related to mitochondria and protein degradation dysfunction, and formation of neurotoxic aggregates of alpha synuclein. This survey of neurotoxin modeling—highlighting newer technologies and implicating a variety of processes and pathways related to mechanisms attending PD—is focused on research studies from 2012 to 2014.

Keywords

Parkinson’s disease 6-Hydroxydopamine MPP+ MPTP Ortho-quinones Reactive oxygen species Rotenone 

Abbreviations

Δψm

Mitochondrial membrane potential

1MeTIQ

1-Methyl-1,2,3,4-tetrahydroisoquinoline

3-Me-N-proTIQ

3-Methyl-N-propargyl-TIQ

5-HT

5-Hydroxytryptamine, serotonin

6-OHDA

6-Hydroxydopamine

AIF

Apoptosis-inducing factor

AMP

Adenosine monophosphate

AMPK

AMP activated protein kinase

ASK1

Apoptosis signal-regulating kinase 1

ATF

Activating transcription factor

BDNF

Brain-derived neurotrophic factor

Ca2+

Calcium ion

CHOP

C/EBP homologous protein

COX

Cyclooxygenase

DA

Dopamine

DAT

Dopamine transporter

l-dopa

l-3,4-Dihydroxyphenylalanine

DOPAC

l-3,4-Dihydroxyphenylacetic acid

EP1 receptor

Prostaglandin E subtype 1 receptor

ER

Endoplasmic reticulum

ERK

Extracellular signal-regulated kinase

GDNF

Glial-derived neurotrophic factor

GFAP

Glial fibrillary acidic protein

GRP78

Glucose regulatory protein 78

HO-1

Heme oxygenase-1

Hsp

Heat shock protein

hUCP2

Human uncoupling protein

HVA

Homovanillic acid

IL

Interleukin

MAPK

Mitogen-activated protein kinase

MPP+

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridinium ion

MPTP

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

mTOR

Mammalian target of rapamycin

NADPH

Reduced nicotinamide adenine dinucleotide phosphate

NOS

Neuronal nitric oxide synthase

PARP

Poly-ADP-ribose polymerase

PD

Parkinson’s disease

p-ERK

Phosphorylated ERK

PGE

Prostaglandin E

Pink

PTEN-induced kinase

PKA

cAMP-dependent protein kinase A

PPAR

Peroxisome proliferator-activated receptor

RESP

Regulated endocrine-specific protein

ROS

Reactive oxygen species

S1P

Sphingosine-1 phosphate

S6K1

p70 S6 kinase 1

SNpc

Pars compacta Substantia nigra

TH

Tyrosine hydroxylase

TH-ir

Tyrosine hydroxylase immunoreactivity

TIQ

1,2,3,4-Tetrahydroisoquinoline

TNF-α

Tumor necrosis factor- α

TRAP

TNF receptor-associated protein

UCHL-1

Ubiquitin carboxy-terminal hydrolase L-1

VEGFR-2

Vascular endothelial growth factor receptor-2

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Molecular and Clinical Pharmacology, ICBM, Faculty of MedicineUniversity of ChileSantiago 7Chile
  2. 2.Department of Biomedical Sciences, Quillen College of MedicineEast Tennessee State UniversityJohnson CityUSA

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