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MPTP Neurotoxicity: Actions, Mechanisms, and Animal Modeling of Parkinson’s Disease

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Handbook of Neurotoxicity

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Abstract

The study of neurotoxicity induced by MPTP led to drastically change the perspective on Parkinson’s disease. In fact, the selective neurotoxicity induced by MPTP rejuvenated PD research and generated a number of studies aimed at elucidating the mechanisms of action of MPTP. Remarkably, these molecular mechanisms turned out to be critical also for the survival of DA neurons in idiopathic PD. In this chapter, the main concepts developed over the last three decades to understand key molecular steps which are pivotal in MPTP toxicity are reported. This is the case of the role played by DAT and VMAT-2 in conditioning the sensitivity to MPTP neurotoxicity. Similarly, the mitochondria as targets of MPTP toxicity appear similarly affected by selective mutation of genes leading to PD. Again, the fate of mitochondria and the ability to clear these organelles when being dysfunctional are key in the modulation of MPTP toxicity. This also applies for misfolded proteins such as alpha-synuclein. Again, multiple brain areas as well as peripheral sites are increasingly recognized to be affected both during MPTP toxicity and sporadic PD patients. Nowadays, it seems that MPTP per se did not lead to the discovery of the environmental compound which causes PD; nonetheless, the study of MPTP did disclose several molecular and cellular pathways which are critical in the genesis of PD. This latter point fairly corresponds to what enthusiastically is expected from MPTP when it was identified as a causal agent of what it remains, a toxic form of environmental parkinsonism.

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Abbreviations

AMPA:

Alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid

ATG:

Autophagy

ATP:

Adenosine triphosphate

BBB:

Blood–brain barrier

COX:

Cyclooxygenase

DA:

Dopamine

DAT:

DA transporter

DSP-4:

N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine

EAA:

Excitatory amino acids

ENS:

Enteric nervous system

GI:

Gastrointestinal

GSH:

Glutathione

i.c.v.:

Intracerebroventricular

IP3:

Inositol(1,4,5)trisphosphate

JNK:

c-Jun N-terminal kinase

KO:

Knockout

LC:

Locus coeruleus

MAO-B:

Monoamine oxidase type B

METH:

Methamphetamine

MK-801:

Dizocilpine

Mn-SOD:

Manganese superoxide dismutase

MPDP+:

1-Methyl-4-phenyl-2,3-dihydropyridine

MPP+:

1-Methyl-4-phenylpyridinium

MPPP:

1-Methyl-4-phenyl-4-propionoxy-piperidine

MPT:

Mitochondrial permeability transition

MPTP:

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

NAD:

Nicotinamide adenine dinucleotide

NE:

Norepinephrine

NET:

NE transporter

NMDA:

N-Methyl-D-aspartate

NMR:

Nuclear magnetic resonance

NO:

Nitric oxide

NST:

Nucleus of the solitary tract

PD:

Parkinson’s disease

PET:

Positron emission tomography

ROS:

Reactive oxygen species

RVLM:

Rostral ventral-lateral medulla

SNpc:

Substantia nigra pars compacta

SOD:

Superoxide dismutase

TH:

Tyrosine hydroxylase

TNF-α:

Tumor necrosis factor alpha

UP:

Ubiquitin–proteasome

UTR:

Untranslated region

VMAT-2:

Vesicular monoamine transporter type 2

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  1. Human Anatomy, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy

    Michela Ferrucci & Francesco Fornai

  2. I.R.C.C.S Neuromed, Pozzilli, IS, Italy

    Francesco Fornai

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Ferrucci, M., Fornai, F. (2021). MPTP Neurotoxicity: Actions, Mechanisms, and Animal Modeling of Parkinson’s Disease. In: Kostrzewa, R.M. (eds) Handbook of Neurotoxicity. Springer, Cham. https://doi.org/10.1007/978-3-030-71519-9_239-1

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