Omi/HtrA2 and neurodegeneration

In connection with neurodegenerative disorders such as Alzheimer´s, Huntington´s and Parkinson´s disease (PD), Omi/HtrA2 has gained much importance in recent years. It already has been shown that complete loss of Omi/HtrA2 protein leads to neurodegeneration (Martin et al., 2004), but the exact mechanism leading to neural loss still remains unknown. Recently three Parkinson’s disease-associated variants in Omi/HtrA2 have been discovered (A141S, G399S, R404W) in PD patients by our group (Strauss et al., 2005) and subsequently in studies conducted in the Belgian population  (Bogaerts et al., 2007). We found that PD-associated variants in the Omi/HtrA2 protein lead to loss of protease function in vitro and impair mitochondrial function in dopaminergic neuronal cells (DFG-supported project KR2119/3-1). Based on this clinical evidence we took the opportunity to generate transgenic mice overexpressing Omi/HtrA2 wild type, and two PD associated mutants of Omi/HtrA2. These transgenic mouse lines overexpressing wild type or mutant Omi/HtrA2 are characterized by behavioural, immunohistochemical and biochemical assays to define the importance of these mutations and Omi/HtrA2 as such in neurodegeneration. In order to further define the role of Omi/HtrA2 in neurodegeneration we additionally validate our findings by in vitro studies using Omi KO cells retransfected with wild type Omi/HtrA2 or mutant of Omi/HtrA2. This study will help us to understand the mechanisms by which this protein is involved in the maintenance of mitochondrial function and dynamics (Kieper et al., 2010; DFG-supported project KR2119/3-2). Therefore we apply various techniques such as live cell imaging, colocalisation studies, determination of mitochondrial mass and mitophagy markers.

Project: Poonam Sood