MPTP Model

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a by-product of the chemical synthesis of a meperidine analog with potent heroin-like effects. MPTP can induce a parkinsonian syndrome in humans almost indistinguishable from Parkinson’s disease (PD). Its recognition as a neurotoxin occurred in early 1982, when several young drug addicts mysteriously developed a syndrome similar to PD after the intravenous use of street preparations of meperidine analogs contaminated with MPTP. Since the discovery that MPTP causes parkinsonism in humans and non-human primates as well as in various other mammalian species, it has been used extensively as a model of PD. In humans and non-human primates, MPTP produces an irreversible and severe parkinsonian syndrome that replicates almost all of the features of PD including tremor, rigidity, slowness of movement, postural instability, and even freezing. The responses, as well as the complications to traditional anti-parkinsonian therapies, are virtually identical to those seen in PD. From neuropathological data, we know that MPTP administration causes – as seen in PD, the disruption of mitochondrial oxidative phosphorylation, oxidative stress, degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and loss of striatal dopamine levels. Additionally, an increased expression of inflammatory markers is observed. On the other hand, two typical neuropathological features of PD have, until now, been lacking in the MPTP model. Firstly, according to most published reports, pigmented nuclei such as locus coeruleus have been spared, except in the SNpc, Secondly, the eosinophilic intraneuronal inclusions called Lewy bodies, characteristic of PD, have not thus far been convincingly observed in MPTP-induced Parkinsonism.

Genetically Modified Animals

Animal models mimicking human diseases are necessary tools to translate knowledge from basic science to applications for patients. Since cause and development of a disease involve multiple factors (i.e. internal-genetic, external-toxic), several different models and, if appropriate, different species (i.e. mouse, primate) need to be examined. For this reason we work on or with the following mouse models:

Parkinsonian phenotype:

  • Toxin-induced
  • 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
  • established
  • Gene-based
  • transgenic ([A30P]α-synuclein)
  • established, in cooperation with P.J. Kahle and C. Haass (Munich)
  • knockout (HtrA2/Omi)
  • established, in cooperation with L.M. Martins and J. Downward J (UK)
  • Point mutations
  • work in progress, in cooperation with N. Brose (MPI Exp. Med., Göttingen)
  • Unknown phenotype (genes involved in neuronal apoptosis)
  • Conditional (time- and/or tissue-specific) gene inactivation
  • Cre/LoxP-recombinase system
  • work in progress, in cooperation with S. Göbbels and K.-A. Nave (MPI Exp. Med., Göttingen)

Animal Behavior

The MPTP mouse model and transgenic mouse models of Parkinson’s disease result in behavioral deficits which will be assessed by two different methods, namely rotarod performance and locomotor activity, either in home cage or a novel environment.

Drosophila

Drosophila melanogaster as animal model for neurodegenerative processes.

The molecular principles underlying neurodegenerative processes are still not fully understood. The histological hallmark of Parkinson’s disease is the presence of intracellular aggregates, of which the protein α-synuclein is one of the major constitutive. In the case of Alzheimer’s disease one finds aggregates of the tubulin associated protein tau. We are using the fruitfly Drosophila melanogaster as an animal model to study the processes within a cell leading to the formation of aggregates and/or cell death.

In this context, our main focus is to produce and analyze highly toxic variants of α-synuclein in its relation to neurodegenerative processes.