MitoModels

Mitochondria are the powerhouses of cells. Recent investigations suggest that the age-related restriction of the mitochondrial energy balance promotes the development of neurodegenerative diseases such as Alzheimer's and Parkinson's. In this project, a transgenic animal model with mitochondrial deficits is being developed, which should facilitate the development of drugs against neurodegenerative diseases.

Due to the increased life expectancy, the prevalence of neurodegenerative diseases such as Alzheimer's (AD) or Parkinson's disease (PD) will continue to rise in the coming years. At present there is only symptomatic therapy for PD, while even this suffers from a lack of effectiveness (cholinergic therapy approaches) in the case of AD. Consequently, the development of new therapeutic approaches is at the center of drug development. A major obstacle to drug development is the lack of relevant models for predominant sporadic forms of these diseases. Models used so far are based on the analysis of (1) rare, genetically determined familial forms of disease (e.g. amyloid hypothesis), (2) inflammatory processes or (3) neuroprotective mechanisms. So far, no approach has resulted in successful targets based on therapeutic hypotheses. However, studies in cellular systems and animal models suggest that mitochondrial functions play a key role in both AD and PD.

This project is based on the assumption that aging processes such as the age-related restriction of the mitochondrial energy balance contribute to the development of various neurodegenerative diseases, which then manifest themselves in various specific clinical pictures according to further genetic or environmental influences. Consequently, an animal model with restricted mitochondrial functions is to be developed for neurodegenerative diseases. For this purpose, RNA interference methods are used for the development of transgenic rats in which the expression of key mitochondrial enzymes is reduced. In addition to the phenotyping of the new model, the influence of known pharmacological inhibitors or RNAi constructs against GSK3beta or CDK5 on the brain will be examined.

At the NMI, lentiviral shRNA vectors are generated to reduce the expression of mitochondrial genes as well as GSK3beta and CDK5. GSK3beta and CDK5 are known targets for AD. Suitable constructs against mitochondrial genes are used to generate transgenic rats. These rats are in turn phenotyped at the NMI with regard to histological characteristics (qualitative and quantitative analysis of synapses in brain slices). They will also be used to examine the histological contribution of the known AD targets GSK3beta and CDK5 after RNA interference in the new animal model.