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  • Review Article
  • Published:

Experimental models of Parkinson's disease

Nature Reviews Neuroscience volume 2, pages 325–332 (2001)Cite this article

Key Points

  • Parkinson's disease (PD) is the second most common neurodegenerative disease. It is characterized by degeneration of dopamine neurons in the substantia nigra and by the presence of intracytoplasmic inclusions known as Lewy bodies, which contain a protein known as α-synuclein. Several animal models of this neurodegenerative disorder have been developed. Each of them has strengths and limitations, which are the focus of this review.

  • An ideal model of PD should have the following characteristics: 1) A normal complement of dopamine neurons at birth with selective and gradual loss of commencing in adulthood. 2) Easily detectable motor deficits, including bradykinesia, rigidity and resting tremor. 3) It should show the development of Lewy bodies. 4) If the model is genetic, it should be based on a single mutation to allow for the robust propagation of the mutation. 5) It should have a relatively short disease course of a few months, allowing rapid screening of therapeutic agents.

  • Injection of 6-hydroxydopamine into the substantia nigra is an early model of PD. This drug kills dopamine neurons owing to the generation of free radicals. This model has been useful for pharmacological screening but it is not characterized by the gradual loss of neurons nor by the formation of Lewy bodies. However, a significant advantage of this model is the presence of a quantifiable motor deficit — rotation.

  • A model based on the injection of rotenone has also been developed. This toxin likely kills neurons by oxidative damage. The rotenone model is characterized by a progressive degeneration of nigrostriatal neurons, by the presence cytoplasmic inclusions reminiscent of Lewy bodies and by the appearance of motor deficits. It suffers, however, from a large variability in susceptibility of individual animals to the toxin, a variability that precludes usefulness of the model to test neuroprotective agents.

  • A novel model of PD was produced by expressing α-synuclein in Drosophila melanogaster. A subset of dopamine neurons disappeared in the mutant flies. Inclusions that resembled Lewy bodies were also observed, and the flies developed locomotor dysfunction with age, although it is not clear whether the motor deficits are due to dopamine dysfunction. In addition, no differences in toxicity were observed between wild-type and mutant α-synuclein expression. But the main advantage of this model is the well-characterized genetics of Drosophila, which will allow for the characterization of enhancer and suppressor mutations.

  • Transgenic mice overexpressing α-synuclein under the control of a Thy-1 promoter show progressive loss of motor function and the accumulation of Lewy-body-like inclusions although not in substantia nigra. This model therefore produces some aspects of the pathology of dementia with Lewy bodies, but it does not faithfully replicate PD.

  • A model based on MPTP toxicity in primates replicates all the clinical signs of PD, including tremor, rigidity, akinesia and postural instability. The substantia nigra is particularly vulnerable to the generation of free radicals that is caused by the drug. The main difficulty with MPTP, however, is that it is an acute or subacute process. In addition, Lewy-body-formation is also absent.

  • Available models of PD have contributed greatly to our understanding of the pathophysiology and potential therapeutics for this condition but, on the basis of the five basic considerations put forward as the hallmarks of an ideal model, it is clear that this model is not available yet. Advances in genetics will probably lead to improved models of PD over the next few years. This will contribute to an improved understanding of the pathophysiology of this condition, as well as to the development of novel therapeutic strategies.

Abstract

Research into the pathogenesis of Parkinson's disease has been rapidly advanced by the development of animal models. Initial models were developed by using toxins that specifically targeted dopamine neurons, the most successful of which used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a toxin that causes parkinsonism in man. More recently, the identification of α-synuclein mutations as a rare cause of Parkinson's disease has led to the development of α-synuclein transgenic mice and Drosophila. Here, I discuss the merits and limitations of these different animal models in our attempts to understand the physiology of Parkinson's disease and to develop new therapies.

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Figure 1: Lewy bodies are a characteristic feature of Parkinson's disease.
Figure 2: Pathogenesis of neuronal dysfunction produced by neurotoxins that affect dopamine neurons.

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Acknowledgements

The secretarial assistance of Sharon Melanson is gratefully acknowledged. This work was supported by the National Institutes of Health, the Department of Defense, The Parkinson's Disease Foundation, The ALS Association, The Hereditary Disease Foundation and The Huntington's Disease Society.

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  1. Department of Neurology, New York Hospital-Cornell Medical Center, 525 East 68th Street, New York , 10021, New York, USA

    M. Flint Beal

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DATABASE LINKS

Parkinson's disease

α-synuclein

ubiquitin

parkin

caspase-3

Bax

Bcl-2

caspase-1

XIAP

GDNF

p53

JNK

cyclooxygenase-2

phospholipase A2

adenosine A1 receptor

dopamine D2 receptor

amyotrophic lateral sclerosis

Huntington's disease

ENCYCLOPEDIA OF LIFE SCIENCES

Parkinson disease

Glossary

BRADYKINESIA

Slowing of and difficulty in initiating movement that is characteristic of Parkinson's disease.

AMPHETAMINE

Molecule that inhibits dopamine uptake and increases the level of this transmitter in the cleft. Its intake by normal subjects induces a psychotic state.

POLYMORPHISM

The simultaneous existence in the same population of two or more genotypes in frequencies that cannot be explained by recurrent mutations.

ROTAROD TEST

Motor test that probes the ability of rodents to keep their balance on a cylinder that rotates continuously at a slow speed, commonly 5–6 revolutions per minute.

LENTIVIRUSES

A group of retroviruses that include HIV. Virus derivatives that are engineered to be replication-defective can be used as expression vectors. Lentiviral vectors have advantages over retroviral vectors because of their ability to infect non-dividing human cells, particularly neurons.

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Beal, M. Experimental models of Parkinson's disease . Nat Rev Neurosci 2, 325–332 (2001). https://doi.org/10.1038/35072550

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