Neurodegenerative disorders, like Huntington’s disease (HD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD) are not only characterized by neuronal death and loss of neuronal function but also by neuroinflammation. Microglia cells, the resident macrophages of the brain, play a central role in this neuroinflammation. The main functions of microglia are tissue maintenance and immune regulation. For this they are constantly surveying their environment. Almost any disturbance in the cellular environment will lead to microglia activation. Activated microglia are therefore a very early hallmark of neurodegenerative diseases. Furthermore this microglia activation often correlates with disease progression. Microglia activations might be beneficial and/or harmful for the surrounding neuronal tissue. For neurodegenerative diseases it is not yet known if the associated microglia activation is beneficial or harmful. Studies on ALS mice suggest that mutations that cause the disease and that are expressed by microglia cells induce a harmful microglia activation that speed disease progression. Targeting specifically this harmful microglia activation would be of great therapeutic value.

In addition to microglia activation neurodegenerative disorders are also characterized by mitochondrial dysfunction. In neurological disease like HD and PD as well as in aging the mitochondrial dysfunction is mediated by an inhibition of the transcriptional co-activator PGC-1a (PPAR g coactivator-1). PGC-1a belongs to the PGC-family of metabolic master regulators and induces the expression of mitochondrial proteins. PGC-family regulated genes very important for inflammatory responses, especially for a specific anti-inflammatory response of macrophages, the alternative activation or M2 activation. We have recently shown that mitochondrial function is essential for this alternative activation in microglia (Ferger et a., 2010).

Our group focuses on the mechanisms by which mutations that are linked to neurodegenerative diseases, especially to ALS and HD, modulate the activation of microglia. For this we focus on the link between mitochondrial dysfunction and inflammatory responses with regard to the PPAR and PGC-system. We hope to identify a mechanism in neurodegenerative diseases that links the mitochondrial dysfunction directly to the harmful microglia activation making this mechanism a valuable target for therapeutics.