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Eyeless – Parkinson disease model without eyes?


Parkinson’s disease (PD) is a degenerative disorder of the central nervous system. It is characterized by the loss of the dopamine producing (dopaminergic) neurons in the Substantia nigra, a dark coloured structure in the midbrain. The pigment melanin, which is also produced in dopaminergic neurons, is responsible for the dark colour of the Substantia nigra. While PD progresses, the Substantia nigra gradually loses its dark colour due to the loss of dopaminergic neurons. Much more important is however that the transmission of information to the cerebral cortex is impaired. Dopamine mediates the fine tuning of muscle movements which is not possible without the neurotransmitter. PD specific symptoms first appear when the dopamine level is reduced by 70 to 80%.

Existing mouse models for PD only reflect certain aspects of the pathology of the disease such as the motor symptoms as a result of the loss of dopaminergic neurons (e.g. tremor), but not other important non-motor symptoms such as gastrointestinal dysfunction or pain.

A novel mouse mutant carrying a mutation in the gene Pitx3, a gene with important functions during embryonic development, seems to present more clinical symptoms of PD than previously analysed PD models. Studies in humans showed that certain sequences of Pitx3 are associated with the development of sporadic forms of PD. The most eye-catching characteristic of variations in the Pitx3 gene are defects in the development of the eyes – in mice as well as in humans.

The newly discovered mutation in Pitx3 was provisionally called “eyeless” due to missing eyes. The difference to the wild-type gene lies in one additional base in the sequence of the gene leading to a completely different protein. “Eyeless” mice were analysed in the German Mouse Clinic to investigate the consequences of the mutation.

“Eyeless” mice have closed eye lids and incomplete eyes behind. During the detailed analysis it turned out that the mice have many more alterations compared to wild-type mice. As in PD the number of dopaminergic neurons in the Substantia nigra is strongly reduced. The mutant mice had reduced body weight, tend to incorporate fat in the liver and are more sensitive to pain. Furthermore, their muscular strength is reduced and behavioural differences could be observed. Female mutants move less and behave more anxiously than wild-type mice while male mutants show the opposite behaviour: they were less anxious and showed stronger arousal.

The comprehensive analyses of the new eyeless mutation in mice within the German Mouse Clinic revealed that this is the first mouse model for PD which not only shows the motor symptoms but also important non-motor symptoms such as increased sensitivity to pain and alterations in the metabolism. Therefore the eyeless mutation might be a promising model to further investigate Parkinson’s disease as well as for novel therapeutic approaches of Dopa-nonresponsive symptoms.


Microphthalmia, parkinsonism, and enhanced nociception in Pitx3416insG mice“, Rosemann et al, Mamm. Genome 2009, DOI 10.1007/s00335-009-9235-0


For further information pleas contact
Prof. Dr. Jochen Graw
Phone: +49 (0)89 3187 2610
Email: grawnoSp@m@helmholtz-muenchen.de